1-[(1-, 2- and 3-indolyl)-lower]piperazine derivatives and intermediates and processes for the preparation thereof



United States Patent Sydney Archer, Bethlehem, N.Y., assignor to terlingDrug Inc., New York, N.Y., a corporation of Delaware No Drawing. FiledSept. 25, 1959, Ser. N 842,203 69 Claims. (Ci. 260-268) This inventionrelates to 1-[(1-, 2- or 3-indolyl)-loweralkynpiperazines, 1-[(1-, 2- or3-indolyl)-loWer-alkyl] homopiperazines, 1 [w (3indolyl)-w-hydroxy-loweralkyl]piperazines, 1 [w (3 indolyl)w-hydroxy-loweralkyl]homopiperazines, their acid-addition and quaternaryammonium salts and to intermediates and processes for the preparationthereof.

3-indolyl-lower-alkylamines are known. The invention here resides in theconcept of attaching a l-piperazinyllower-alkyl group or al-homopiperazinyl-lower-alkyl group to the l-, 2-, or 3-position of theindole nucleus or a l-piperazinyl-w-hydroXy-loWer-alkyl group or al-homopiperazinyl-w-hydroxy-lower-alkyl group to the 3-position of theindole nucleus. It is also concerned with certain novel intermediatesand with processes for making such intermediates and for making saidl-[(1-, 2- and 3-indolyl)-lower-alkyl]piperazines, l-[1-, 2- or3-indo1yl)- lower-alkyl] homopip erazines, l- [w- S-indolyl)-w-hydroxylower-alkylJ-piperazines and1-[w-(3-indolyl)-Q-hydroxyloweralkyl]homopiperazines.

A. preferred aspect of my invention relates to compounds having theformulae:

wherein R is a hydrogen atom or one or more substituents selected fromthe group consisting of halogen (including fluorine, chlorine, bromineand iodine), loweralkyl, lower-alkoxy, hydroxy, methylenedioxy,ethylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl,loweralkyl-sulfonyl, trifluoromethyl, monocarbocyclic aryllower-alkoxyand lower-alkanoyloxy; R is a hydrogen atom or a lower-alkyl,hydroxy-lower-alkyl, monocarbocyclic aryl, moncarbocyclicaryl-lower-alkyl, bis(mono- "Ice carbocyclic aryl)-lower-alkyl,monocarbocyclic aryl-lower alkenyl or heteromonocyclic radical; R is ahydrogen atom or a lower-alkyl or monocarbocyclic aryl radical; R is ahydrogen atom or a lower-alkyl, monocarbocyclic aryl, monocarbocyclicaryl-lower-alkyl or a monocarbocyclic aryl-loWer-alkenyl radical; R andR are hydrogen atoms or each of R and R can represent a loweralkylradical or one of R and R can represent a loweralkyl radical while theother of R and R represents a hydrogen atom; X is a hydrogen atom or thehydroxyl radical and represents the hydroxyl radical only when thehydroxyl radical and the l-nitrogen atom'of the piperazine ring areseparated by at least two carbon atoms, that is When n in Formula la isat least 2; n represents an integer from one toseven; and m representsthe integers 1 or 2.

In the above general Formulae la, b and c, R represents a hydrogen atomor one or more substituents selected from the group consisting ofhalogen, lower-alkyl, lower-alkoxy, hydroxy, methylene-dioxy,ethylenedioxy, lower-alkylrner capto, lower-alkylsulfinyl,lower-alkylsulfonyl, trifiuoromethyl, monocarbocyclic aryl-lower-alkoxyand loweralkanoyloxy. R can represent from one to four of the abovesubstituents which can be on any of the four available positions on thebenzene ring, and when more than one substituent is present, they can bethe same or difierent. When R represents a lower-alkyl, lower-alkoxy,lower-alkylmercapto, lower-alkyl-sulfinyl, lower-alkylsulfonyl orlower-alkanoyloxy radical, it can be either straight or branched and cancontain from one to about five carbon atoms, and when R represents amonocarbocyclic aryllower-alkoxy radical, it can contain from seven toabout ten carbon atoms and can be further substituted by from one tothree substituents of the nature named above, i.e., halogen,lower-alkyl, loWer-alkoxy, hydroxy, methylenedioxy, ethylenedioxy,lower-alkyl-mercapto, loWer-alkyL sulfinyl, lower-alkylsulfonyl,trifluoromethyl and loweralkanoyloxy. R thus stands, inter alia, forfluoro, chloro, bromo, iodo, methyl, ethyl, butyl, methoxy, dimethoxy,trirnethoxy, ethoxy, ethoXy-methoxy, butoxy, hydroxy, methylenedioxy,ethylenedioxy, methylmercapto, isopropylmercapto, methylsulfinyl,isopropylsulfinyl, methylsnlionyl, isopropylsulfonyl, trifiuoromethyl,benzyloxy, 3,4,5- trimethoxybenzyloxy, acetoxy or isobutyryloxy.

In the above general Formulae, Ia, b and 0, R rep resents a hydrogenatom or a loWer-alkyl, hydroxy-loweralkyl, monocarbocyclic aryl,monocarbocyclic aryl loweralkyl, bis(monocarbocyclic aryl)-lower-alkyl,'rnonocarbocyclic aryl-lower-alkenyl or heteromonocyclic radical; Rrepresents a hydrogen atom or a lower-alkyl or monocarbocyclic arylradical; and R represents a hydrogen atom or a loWer-alkyl,monocarbocyclic aryl, monocarbocyclic aryl-loWer-alkyl ormonocarbocyclic aryl-loweralkenyl radical. When R R or R, represents aloweralkyl radical, it can be straight or branched and can contain fromone to about six carbon atoms. R R and R thus stand, inter alia, formethyl, isopropyl, isobutyl or n-hexyl.

When R represents an hydroxy-lower-alkyl radical, it can be straight orbranched, can contain from two to about six carbon atoms and is suchthat the oxygen and nitrogen atoms are separated by at least two carbonatoms. R thus also stands, inter alia, for Z-hydroxyethyl,3-hydroxy-l-methylpropyl or 6-hydroxyl1exyl.

When R R or R represents a monocarbocyclic aryl radical, or when R or Rrepresents a monocarbocyclic aryl-loWer-alkyl or a monocarbocyclicaryl-lower-alkenyl radical or when R re resents a bis(rnonocarbocyclicaryl)-lower-alkyl radical, each lower-alkyl and loweralkenyl moiety ofsaid radicals can contain up to about four carbon atoms and eachmonocarbocyclic aryl moiety of said radicals can be further substitutedas will be hereinafter described and each monocarbocyclic aryl moiety,together with said substituents, can contain from six to about twelvecarbon atoms. The monocarbocyclic aryl moiety can thus be phenyl orphenyl substituted by one or more substituents selected from the groupconsisting of halogen (including fluorine, chlorine, bromine andiodine), lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy,ethylenedioxy, lower-alkylrnercapto, lower-alkylsulfinyl,lower-alkylsulfonyl and trifiuoromethyl. When the monocarbocyclic arylmoiety is substituted by more than one of the above substituents, thesubstituents can be the same or different and can occupy any of theavailable positions on the phenyl ring. When the substituent is alower-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl orlower-alkylsulfonyl group, said substituents can be either straight orbranched and can contain from one to about four carbon atoms. Thus whenR R or R represents a monocarbocyclic aryl, monocarbocyclic aryl-lower-alkyl, bis(monocarbocyclic aryl)-lower-alkyl or a monocarbocyclicaryl-lower-alkenyl radical, each of R R and R; can represent suchorganic radicals, inter alia, as phenyl, benzyl, phenethyl,4-phenylbutyl, benzhydryl or cinnamyl or such organic radicalssubstituted in the phenyl ring by one or more of such substituents,inter alia, as fluoro, chloro, bromo, iodo, methyl, isobutyl, hydroXy,methoxy, n-butoxy, methylenedioxy, ethylenedioxy, methylmercapto,isopropylmercapto, methylsulfinyl, :isopropylsulfiuyl, methylsulfonyl,isopropylsulfonyl or trifluoromethyl.

In the above general Formulae Ia, b and c when R represents aheteromonocyclic radical, it can represent a heteromonocyclic radicalcontaining one or more heteroatoms such as nitrogen, oxygen or sulfur.Thus R also stands, inter alia, for pyrimidy-l, pyrazinyl, pyridyl,thiazolyl, oxazolyl, 1,3,5-triazinyl, thienyl, and the like.

In the above general Formulae Ia, b and c, R and R represent hydrogenatoms or each of R and R can represent a lower-alkyl radical or one of Rand R can represent a lower-alkyl radical while the other of R and Rrepresents a hydrogen atom. When R and R represent lower-alkyl radicals,they can contain from one to about three carbon atoms, can be straightor branched and can occupy either the 2-, 3-, 5- or 6-position of thepiperazine ring or the 2-, 3-, 5-, 6- or 7-positions of thehomopiperazine ring. R and R thus stand for hydrogen, methyl, ethyl,n-propyl or isopropyl.

In the above general Formulae Ia, b and c, n represents an integer fromone to seven and, in Formula Ia when X is a hydroxyl radical, must be atleast two. The loweralkylene group, C I-I can be straight or branchedand stands, inter alia, for methylene, ethylene, propylene, butylene,Z-methylproplylene, Z-methylbutylene, Z-ethylbutylene, Z-ethylpentyleneand the like.

The compounds of the present invention can be prepared by the followingreactions in which R R R R R R X, n and m have the meanings given above,except that R does not represent a hydrogen atom and Hal represents ahalogen atom and Alk represents a loweralkyl radical. The compounds ofFormulae Ia, b and c where R represents a hydrogen atom are prepared ina manner as will be hereinafter described.

75 Method A above can be used to prepare 1-[(l-, 2- and 3-indolyl)-loweralkyl]-4-substituted-piperazines and l- 1-, 2- andB-indolyl)-lower-alkyl]-4-substituted homopiperazines of Formula la, bor c where X in Formula In is a hydrogen atom. The intermediateindolyl-loweralkyl halides of Formula Ila, b or c, used as startingmaterials in Method A above, are prepared by reduction of an indolyl 2-or 3-carboxylic acid or an indole 1-, 2-, or 3-alkanoic acid withlithium aluminum hydride and conversion of the resulting alcohol to thecorresponding halide by reacting the former with, for example, aphosphorus trihalide or a thionyl halide. The (1-, 2- and 3-indolyl)-lower-alkyl halides thus produced are reacted with an appropriatel-substituted-piperazine or l-substituted homopiperazine at atemperature between about 50 C. and 150 C. in the presence of anacid-acceptor. The reaction is preferably carried out in an organicsolvent, inert under the conditions of the reaction, such as anhydrousethanol, benzene, xylene and the like. The purpose of the acid-acceptoris to take up the hydrogen halide which is split out during the courseof the reaction. The acid-acceptor is a basic substance which formswater soluble by-proclucts easily separable from the main product of thereaction and includes such substances as alkali metal salts of weakacids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate,sodium acetate, sodium alkoxides, and the like. The acid-acceptor canalso be in the form of. an excess quantity of thel-substituted-piperazine or lsubstituted-hornopimrazine. Y

The compounds of Formula Ia where X is H and n is at least 2 can also beprepared by reacting an indole with a 1-(w-hydroxy-lower-alkyl)-r-substituted piperazine or a 1(w-hydIOX-lower-alkyl)-4-substituted-homopipe azine in the presence of a Raneynickel catalyst. The reaction is preferably carried out in an organicsolvent inert under the conditions of the reaction, such as xylene,cymene or di-n-butyl ether, and the like.

Method B above can be used to prepare l-[2-(3-indolyD-ethyl 4substituted-piperazmes, I-[Z-(B-indolyl) ethyl]-4-substituted-homopiperazines, l- [2- 3-indolyl -2- hydroxyethyl] 4substituted-piperazines and l-[2-(3-indolyl) 2hydroxyethyl]-4-substituted-homopiperazines, i.e. compounds of formulaIa where n is 2 and X is a hydrogen atom or a hydroxyl radical. Theintermediate indoles used as starting materials in Method B above areprepared by known methods, for example by the Fischer indole synthesisusing an appropriate substituted phenylhydrazine and a methyllower-alkyl ketone or a methyl monocarbocyclic aryl ketone.Alternatively the starting indoles can be prepared by catalyticreduction of a [3,2- clinitrostyrene. with a glyoxalyl halide at atemperature in the range from about C. to C. in an organic solvent inertunder the conditions of the reaction, such as ether, petroleum ether,dioxane, tetrahydrofuran and the like, thus affording the3-(indolyl)-glyoxalyl halides of Formula Illa. A preferred solvent isether. The 3-(indolyl)glyoxalyl halides of Formula Illa thus preparedare then reacted with a l-substituted-piperazine or al-substituted-homopiperazine at a temperature between about 5 C. andabout C. in the presence of an acid-acceptor to give the l-[ (S-indolyl)-glyoxalyl] 4 substituted-piperazines and 1-{ (3-indolyl) glyoxalyl] 4substituted-homopiperazines of Formula RM. The reaction is preferablycarried out in an organic solvent, inert under the conditions of thereaction, such as tetrahydrofuran, ether, ethylene dichloride and thelike. The purpose of the acid-acceptor is to take up the hydrogen halidewhich is split out during the course of the reaction. The acid-acceptoris a basic substance which forms water-soluble by-products easilyseparable from the main product of the reaction and includes suchsubstances as alkali metal salts of weak acids, e.g., sodium carbonate,sodium bicarbonate, potassium carbonate, sodium acetate, and the like.The acid-acceptor can also be in theform of an excess quantity of theThe indoles thus prepared are reacted l-substituted-piperazine or1-substituted-homopiperazine. A preferred solvent is tetrahydrofuran andit is preferred to use an excess quantity of thel-substituted-piperazine or 1-substituted-homopiperazine as theacid-acceptor. The

1-[(3-indolyl)glyoxalyl] -4-substituted piperazines and 1-[(3-indolyl)glyoxalyl] 4 substituted-homopiperazines thus prepared arereacted with an alkali metal aluminum hydride at a temperature betweenabout 0 C. and about 65 C. in an organic solvent inert under theconditions of the reaction, for example, ether or tetrahydrofuran. It ispreferred to use lithium aluminum hydride in refluxing tetrahydrofuran.

Method B affords compounds of Formula I where thepiperazinyl-lower-alkyl, homopiperazinyl-lower-alkyl,piperazinyl-w-hydroxy-lower-alkyl or homopiperazinyl-whydroxy-lower-alkyi group is attached to the 3-position of the indolenucleus. When R in compounds of Formula lVa is a hydrogen atom, the mainproduct is a l-[2-(3- indolyl)ethyl]-4-substituted-piperazine or a1-[2-(3-in- 'dolyl)ethyl]-4substituted-homopiperazine, i.e., la, whereinX is H and n is 2, although it is possible to obtain both1-[2-(3-indolyl)-2-hydroxyethyl] 4 substituted-piperazines or1-[2-(Z-lndolyl)-2-hydroxyethyl]-4-substituted homopiperazines and1-[2-(3-indolyl)ethyl] -4-substitutedpiperazines or1-[2-(3-indolyl)ethyl]-4-substituted-homopiperazines. However, when R;in compounds of Formula No is a lower-alkyl, monocarbocyclic aryl,monocarbocyclic aryl-lower-alkyl or a monocarbocyclic aryllower-alkenylradical, the only products obtained on reduction with an alkali metalaluminum hydride are the corresponding l- [2- B-indolyl-2-hydroxyethyl'] -4-substituted-piperazines and1-[2-(3-indolyl)-2-hydroxyethyl]-4- substituted-homopiperazines, i.e.,la, X is OH. It is nevertheless possible to obtain1-[w-(3-indolyl)-w-hydroxy-lower-alkyl]-4-substitutedpiperazines andl-[w-(3-indolyl)- w-hydroxy-lower-alkyl]-4-substituted-homopiperazinesof Formula Ia wherein R4 is H by another method as will be hereinafterdescribed. 1

Method C can also be used to prepare compounds of general Formula Iawhere the piperazinyl-w-hydroxylower-alkyl group,homopiperazinyl-w-hydroxy-loweralkyl group, piperazinyl-lower-alkylgroup or the honiopiperazinyl-lower-alkyl groupis attached to the3-position of the indole nucleus. The starting indole Grignard reagentis prepared by reacting an indole having no substituent in the1-position of the indole nucleus with a loweralkylnragnesiurn halide inan appropriate organic solvent, for example ether or tetrahydrofuran,and reacting the resulting indolemagnesium halide with a4-substituted-lpiperazinyl-lower-alkanoyl halide or a4-substituted-1-homopiperazinyl-lower-alkanoyl halide to give thel-{cJ-(lr.

azines and 1-{w-(3-indolyl) w hydroxyl-lower-alkyl] )-4-substituted-homopiperazines can be obtained, i.e., Ia, X is OH, R, is H.The reaction is preferably carried out in an organic solvent inert underthe conditions of the reaction,

' for example methanol, ethanol, ether, tetrahydrofuran and the like.Alternatively, the compounds of Formula Va can bereacted with alower-alkyl halide, a monocarbocyclic aryl-lower-alkyl halide or amonocarbocyclic aryllower-alkenyl halide in the presence of anacid-acceptor to give the 1-[w-(3-indolyl)-w-keto-lower-alkyl]-4-substituted-piperazines and thel-[w-(3-indolyl)u;-keto-loweralkyl]-4-substituted-homopiperazines ofFormula Via Where R is not a hydrogen atom. The purpose of theacid-acceptor is to take up the hydrogen halide which is split outduring the course of the reaction. The reaction is preferably carriedout in liquid ammonia in the presence of an alkali metal amide, forexample, sodium amide. The compounds of Formula VIa thus prepared canthen be reacted with an alkali metal aluminum hydride or an alkali metalborohydride as described above, preferably lithium aluminum hydride orsodium borohydride, to give l-[w-(3-indolyl)-w-hydroxy-lower-alkyl] 4substitutedpiper-azines and 1-[w( 3-indolyl) -w-hydroxy,alkyl]4-substituted-homopiperazines of Formula Ia where X is OH.

Method D above can be used to prepare l-[(1-, 2 and3-indolyl)-lower-alkyl] 4 substituted-piperazines and 1- [(l-, 2- and3-indolyl)-lower-alkyl]-4-substituted-homopiperazines of Formula Ia, bor c where X is H and n is an integer from one to seven. Theintermediate mixed anhydrides used as starting material are prepared byreacting a 1-, 2- or 3-indolyl-lower-alkanoic acid or a 2- or3-indolecarboxylic acid with a lower-alkyl-haloformate in the presenceof an acid-acceptor, for example triethylamine, at a temperature betweenabout 20 C. to about 20 C. The reaction is preferably carried out in anorganic solvent inert under the conditions of the reaction such asanhydrous acetone, ether, ethylene dichloride and the like. Acetone isthe preferred solvent. The purpose of the acid-acceptor is to take upthe hydrogen halide split out during the course of the reaction and is abasic substance which forms water-soluble by-products easily separablefrom the product. The indolyl-lower-alkane mixed anhydrides of the 1-,2- and 3-indole-lower-alkanoic acids, and the 2-indolecarboxylic acidsand 3-indolecarboxylic acids thus formed in situ are reacted with'anappropriate l-substituted-piperazine or l-substituted-homopiperazine ata temperature between about 20 C. and about 20 C. to give the l-[(1-, 2-and 3-indolyl)-a-ketolower-alkyl]-4-substituted-piperazines, l[(l-, 2-and 3- indolyl) on lreto-lower-alkyl] -4-substituted homopiperazines,1-(2-indolylcarbonyl)-4-substituted-piperazines, 1- (2indolylcarbonyl)-4-substituted-homopiperazines, l-(3-indolylcarbonyl)-4-substituted-piperazines and the 1(3- indolylcarbonyl)4 substituted-homopiperazines of Formulae VIIa, b and c. The latter onreaction with an alkali metal aluminum hydride as described above,preferably lithium aluminum hydride, afford compounds of Formula Ia, bor wherein X is H and n is an integer from one to seven.

Alternatively the 1- (fa-indolyl) -a-keto-lower-alkyl] -4-substituted-piperazines and 1-[(3 -indolyl)-a-keto-loweralkyl] 4substituted-homopiperazines of Formula VIIa where R; is hydrogen can beprepared by reacting an indole having no substituent in the l-positionof the indole nucleus with a lower-alkyl magnesium halide in anappropriate organic solvent, for example ether or tetrahydrofuran, andreacting the resulting indole magnesium halide with al-(halo-lower-alkanoyl)-4-substituted-piperazine or a l-(halo-loweralkanoyl) 4 substituted-homopiperazine thus producing the compounds ofFormula VIIa where R; ishydrogen and n is an integer from two to seven.

Method E above can be used to prepare 1-[ (3-indolyl)- methyl] 4substituted-piperazines and l-[ (3 indolyl)-methyl]-4-substituted-homopiperazines, that is, compounds of Formula Iawhere X is H and n is 1. The 1-[(3-indolyl)methyl] 4substituted-piperazines and 1-[ (3indoly1)methyl]-4-substituted-homopiperazines are prepared by reactingan indole with formaldehyde and an appropriate l-substituted-piperazineor 1-substituted-homopiperazine at a temperature between about 50 C. andabout 150 C. The formaldehyde can be in the form of an aqueous solution,i.e., 40% formalin solution or a polymeric form of formaldehyde such asparaformaldehyde or trioxymethylene. When such polymeric forms are used,a molar excess of mineral acid such as hydrochloric acid,

is added to regenerate the free aldehyde from the polymer. The reactionis preferably carried out in an organic solvent, inert under theconditions of the reaction, such as ethanol, methanol or3-methylbutanol.

The compounds of Formula la, b or c where R is a hydrogen atom areprepared by reacting with hydrogen in the presence of a catalyst the1-[(1-, 2- and 3-ind0lyl)- lower-alkylJpiperazines, 1-[(l-, 2 and3-indolyl)-loweralkyl] homopiperazines, 1- [w-( 3-indolyl-w-hydroxy-loweralkyl]piperazines or 1 [LU-(3indolyl)-w-hydroxy-loweralkyl]homopiperazines of Formula Ia, b or c inwhich the piperazine or homopiperazine ring bears attached to the4-position a benzyl, benzhydryl or cinnamyl radical. The reaction ispreferably carried out in the presence of a platinum or palladiumcatalyst in an organic solvent inert under the conditions of thereaction, for example ethanol, cellosolve, benzene, toluene and the likeand at hydrogen pressures in the range from about 30 psi. to about psi.The benzyl, benzhydryl or cinnamyl radicals can be unsubstituted orsubstituted in the phenyl ring by substituents of the nature describedabove but which do not take part in or adversely affect the reactionthus excluding such substituents as those containing sulfur, for examplelower-alkyl-mercapto, or halogen. A preferred catalyst ispalladium-on-charcoal and a preferred solvent is ethan01.

In the procedures described above, the piperazine or homopiperazinemoiety is attached as a complete ring to the indolyl moiety eitherthrough a lower-alkyl or loweralkanoyl chain. The compounds of FormulaIa, b or 0 above can also be prepared using the same general proceduresas described above except that the piperazine or homopiperazine ring isclosed after an N-benzyl-N-substituted-lower-alkylenediamine group hasbeen joined to the indolyl moiety through a lower-alkylene or aloweralkanoyl chain. The procedure is particularly adaptable to thepreparation of compounds of Formula Ia, b or 0 wherein R and/ or Rrepresent lower-alkyl radicals. The procedure is illustrated below usingMethod D, but it is to be understood that the other methods describedabove can be used as well. In the following reactions R R R R R R n, m,and Hal have the meanings given above.

In the above procedure an Nabenzyl-N substitutedlower-alkylene diamineis reacted, in the above instance, with a mixed 'anhydride of a 1-, 2-or 3-indole-lovveralkanoic acid or a 2- or 3-indolecanboxylic acid usingthe same conditions as described above in the description of Method Dfor the reaction of an indolyl-lower-alkane mixed anhydride with al-substituted-piperazine or a lsubsti-tuted-homopiperazine thusproducing the compounds of Formula VIIIa, b or c. The lower-alkyleneradical, which is an ethylene radical when m is 1 or a propylene radicalwhen m is 2, can be further substituted by a straight or branchedlower-alkyl radical, R and the lower-alkyl radical can occupy any of thecarbon atoms of the ethylene or propylene radical, although for thepurpose of illustration only it is shown above in Formulae VIIia, b andc on the carbon atom adjacent to the amide nitrogen atom. Compounds ofFormulae Villa, [2 and c wherein R is attached to the carbon atomadjacent to the amide nitrogen atom afford compounds of Formulae Ia, band wherein the lower-alkyl radical is attached to the 2-5p0sition ofthe piperazine ring or the 7-position of the homopiperazine ring.Compounds of Formulae la, b and 0 wherein the lower-alkyl radical isattached to the 3-position of the piperazine ring or the -position ofthe homopiperazine ring can be prepared using anN-benzyl-N-substituted-lower-alltylenediamine bearing a loWer-alkylradical on the carbon atom adjacent .to the tertiary-amino group or byanother alternative procedure as will be hereinafter described, andcompounds of the Formulae la, b and 0 wherein the lower-alkyl r-adicalis attached to the 6-position of the homopiperazine ring can be preparedusing an N-benzyl-N-subst-itutedpropylenediamine bearing a lower-alkylradical on the 2- positicn of the propylene radical.

The compounds of Formulae VIIIa, b and c thus prepared are reacted withan alkali metal aluminum hydride, using the same conditions as describedabove in the description of Methods B, C and D for the reaction ofcompounds of Formulae IVa, Va, VIa, and Vila, b and c with an alkalimetal aluminum hydride, thus producing the corresponding N-(1-, 2- and3-indolyl-lower-alkyl)- N benzyl N substituted lower alky-lenediaminesof Formulae lXa, b .and c. It is preferred to use lithium aluminumhydride. It will be appreciated that Methods A, B, C and E can beadapted to the above-described synthesis as Well and further thatMethods B and C aiford N [w (3 indolyl) w hydroxy lower a kyl] N-benzyl-N'-substituted-lower-al-kylenediamines corresponding to thecompounds of Formulae D01, band 0. That is, it is only necessary tosubstitute for the l-substitutedpiperazine and the1-substituted-homopiperazine used in Methods A, B and E thecorresponding 'N-benzy-l-N-substituted-ethylenediamine andNabenzyl-N-substituted propylenediamine, respectively, or to substitutefor the 4- sub stituted-1-piperazinyl-lower-alleanoyl halide and the 4substituted 1 homopiperazinyl lower alkanoyl halide used in Method C thecorresponding N-(N'-benzyl N substituted ethylenediamino) lower alkanoylhalide and N (N benzyl N substituted propylenedia mino)-lo-wer-alkanoylhalide, respectively, and proceed as will be hereinafter described. Itwill also be appreciated that the latter step involving reaction of theintermediate amide with :an alkali metal aluminum hydride can be omittedwhen using Methods A, C and E. It is only necessary to convert the amideproduced in Methods B and D to the corresponding secondary amine beforeproceeding to the next step.

The N-(1-, 2- and 3-indolyl-lower-alkyl)-N-benzyl-N'-substituted-lower-alkylenediamines corresponding to Formulae iXa, b, andc and the N-[w-(3-indolyl)-w-hydroxylower alkyl] Nbenzyl-N-substituted-loWer-alkylenediamines corresponding to FormulaIXa, thus produced are then reacted with an ocor ,B-halo-lower-alkanoylhalide at a temperature between about 0 C. and C. to give thebenzohalide quaternary ammonium salts of the 1-[(l-, 2- and3-indolyl)-lower-alkyl]-4-substituted-2- piperazinones, 1-[(1-, 2- and3-indolyl)-1ower-alkyl]-4- substituted-Z-homopiperazinones, 1[w-(3-indolyl)-w-hydroxy-lower-alkyl]-4-substituted 2 piperazinones and1- [w-(3-indolyl)-w-hydroXy-lower-alky1] 4 substituted-2-homopiperazinones corresponding to Formulae Xa, b and c. The reactioncan be carried out either with or without the use of an acid-acceptorand is preferably conducted in an organic solvent inert under theconditions of the reaction, for example, methylene dichloride,chloroform, ethylene dichloride, benzene and the like. For the purposeof illustration only, an a-halo-loWer-alkanoyl halide is shown in theabove-described reaction. However, an alternative procedure forpreparing the benzohalide quaternary ammonium salts of the 1-[(l-, 2-and 3-indolyl)- lower-alkyi]-4-substituted-2-homopiperazinones and the1- [w-(3-indolyl) w hydroXy-lower-alkyl]-4-substituted-2-homopiperazinones corresponding to Formulae Xa, b and 0 comprisesreacting an N-(l-, 2- or 3-indolyl-loweralkyl)-N'-benzyl Nsubstituted-ethylenediamine corresponding to Formulae IXa, b and c (mis 1) or an N- [w-(3 indolyl) w hydroXy-loWer-alkyl]-N'-benzyl-N-substituted-ethylenediamine corresponding to Formula Dia (m is l) with aB-halo-lower-alkanoyl halide using conditions similar to those describedabove when an 0:- halo-lower-alkanoyl halide is used. The aorfl-halolower-alkanoyl halides can be straight or branched and thefl-halo-lower-alkanoyl halide can contain loWer-alkyl radicals, R or Ron either the 01,-- or the fl-carbon atom. Thus compounds of FormulaeXa, b and 0 can be obtained wherein R and R can occupy the 3-, 5- or 6-positions of the Z-piperazinone ring, or the 3-, 5-, 6-, or 7-positionsof the 2-homopiperazinone ring or the 2-, 3-, 5- or 6-positions of the7-homopiperazinone ring, and by proper choice of theN-benzyl-N-substituted-lower-alkylenediamine, or the aorB-halo-lower-alkanoyl halide, compounds of the invention can be obtainedwhere R and/or R represent such groups, inter alia, as methyl,

ethyl, propyl or isopropyl.

The benzohalide quaternary ammonium salts of the l- [(1-, 2- and 3indolyl)-lower-alkyl] 4 substituted-2- piperazinones, 1-[(l-, 2- and3-indolyl)-lower-alkyl]-4- substituted-Z- and 7-homopiperazinones,l-[w-(3-indolyl)-' w-hydroxy-lower-alkylj-4-substituted-2-piperazinonesand 1-[w-(3 indolyl)-w-hydroXy-lower-alkyl]-4-substituted2- and7-homopiperazinones corresponding to Formulae Xa, b and c are thencatalytically debenzylated to the corresponding free bases of FormulaeXIa, b and c by reacting the former with hydrogen in the presence of acatalyst at a temperature from about 20 C. to about 70 C. and underhydrogen pressures in the range from about 30 psi. to about 70 p.s.i.The reaction is conducted in an organic solvent inert under theconditions of the reaction,

for example methanol, ethanol or 2-propanol. A preferred catalyst ispalladium-on-charcoal and a preferred solvent is ethanol.

It will be appreciated that, when R represents a benzyl, benzhydryl orcinnamyl radical in the compounds of Formulae Xa, b and c, this radicalcan also be removed by catalytic debenzylation to give compounds ofFormulae XIa, b and c where R is hydrogen. This synthetic methodtherefore provides a second process for preparing compounds of FormulaeIa, b and c where R is hydrogen.

The l-[(l-, 2- and 3-indoly1)-lower-alkyl]-2-piperazinones, 1-[( 1-, 2-and 3-indolyl)-lower-alkyl]-2- and 7- homopiperazinones,l-[w-(B-indolyl) w hydroxy-loweralkyl1-2-piperazinones and 1[w-(3indolyl)-w-hydroxyloweralkyl]-2- and 7-homopiperazinonescorresponding to Formulae XIa, b and c are then reacted with an alkalimetal aluminum hydride, preferably lithium aluminum hydride, usingconditions previously described, to give compounds of Formulae Ia, b andwherein R and/or R is either a hydrogen atom or a lower-alkyl radical.

' Another synthetic procedure which provides access to compounds ofFormulae Ia, b and c wherein R and/or R is hydrogen or a lower-alkylradical is illustrated below by the following reactions wherein R R R RR R 1, m and Hal have the meanings given above except that R does notrepresent hydrogen:

An N-(fior 'y-halo-lower alkyl)-N,N-dibenzylarnine is reacted with aprimary amine, R NH at a temperature between about 50 C. and about 150C. in the presence of an acid-acceptor. The reaction is preferablycarried out in an organic solvent, inert under the conditions of thereaction, such as anhydrous ethanol, benzene, xylene, Z-ethoxyethanol(Cellosolve), and the like. The nature of the acid-acceptor is the sameas that described above in the prepartion of 1-[(l-, 2- and3-indolyl)-loweralkyl]-4-substituted-piperazines and l-[(1-, 2- and3-indolyl)-lower alkyl]-4-substituted-homopiperazines using Method A.The lower-alkyl radical, which is an ethylene radical when'm is l or apropylene radical when m is 2, can be further substituted by a straightor branched lower-alkyl radical, R and the lower-alkyl radical, R canoccupy any of the carbon atoms of the ethylene or propylene radical,although for the purpose of illustration only it is shown above on thecarbon atom adjacent to the tertiary amino group. The compounds ofFormula XII thus produced wherein R is attached to the carbon atomadjacent to the tertiary amino group aliord compounds of Formula Ia, bor 0 wherein the loweralkyl radical, R is attached to the 2-position ofthe piperazine ring or the 7-position of the homopiperazine ring.Compounds of Formula Ia, b or 0 wherein the lower-alkyl radical isattached to the 3-position of the piperazine ring or the 6-position ofthe homopiperazine ring are obtained from compounds of Formula XII whereR is attached to the ,B-carbon atom of the ethylene or propyleneradical, respectively, and the compounds of Formula Ia, b or c where thelower-alkyl radical, R is attached to the 5-position of thehomopiperazine ring are obtained from compounds of Formula XII where thelower-alkyl radical, R is attached to the 'y-carbon atom of thepropylene radical (i.e. m is 2). The homopiperazines can also beprepared by another method as will be hereinafter described.

The 1-(N,N-didenzylamino)-2- or 3-(N-substituted)-lower-alkylene-secondary amines of Formula XII thus produced are reactedwith an 04- or fl-halo-lower-alkanoyl halide using conditions similar tothose described above in the description of the preparation of compoundsof Formula X. The aor B-halo-lower alkanoyl halide can be any uorfi-halodower alkanoyl halide of the type described above in thedescription of the preparation of compounds of Formulae Xa, b and c.

The resulting l-(N,Ndibenzylamino)-2-[N-(uor 5 halo lower alkanyol) N(substituted)] loweralkylenediamines of Formula XIII can be solated andpurified or if desired quaternized in the crude form by refluxing in anappropriate organic solvent inert under the conditions of the reaction,for example ehtanol, acetonitrile or Cellosolve. A preferred solvent isCellosolve.

For the purpose of illustration only, an a-halo-loweralkanoyl halide isshown in the above-described reaction. However, by reacting afi-halo-lower-alkanoyl halide with ethylenediamine derivatives ofFormula XII, the l-benzyl- 4-substituted-S-homopiperazinonescorresponding to Formula XIV can be obtained. The ocor[I-halo-loweralkanoyl halides can be straight or branched and the,B-halo-loWer-alkanoyl halide can contain lower-alkyl radicals, R or Ron either the aor the fl-carbon atom. Thus, by proper choice of the 04-or fi-halo-lower-alkanoyl halide, compounds of Formula XIV aiford, aswill be seen, compounds of Formula la, b or c where a loweralkylradical, R is attached to the 2-position of the piperazine ring or tothe 6- or 7-positions of the homopiperazine ring.

The 1-benzyl-4-substituted-3-piperazinone and l-benzyl-4-substituted-5-homopiperazinone benzohalide quaternary ammonium saltsof Formula XIV thus produced are catalytically debenzylated to thel-substituted-Z-piperazinones and 1substituted-7-homopiperazinones ofFormula XV using the same conditions as described above in thedescription of the preparation of compounds of Formulae XIa, b and c.The 1-substituted-Z-piperazinones and 1-substituted-7-homopiperazinonesof Formula XV can be isolated and purified in the form of the free baseor if desired can be converted to an acid-addition salt for purposes ofpurification and characterization. Appropriate acid-addition salts arethose derived from mineral acids as hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, sulfuric acid and phosphoric acid; andorganic acids such as acetic acid, citric acid, lactic acid, tartaricacid and p-toluenesulfonic acid.

The 1-substituted-2-piperazinones and l-substituted- 7-homopiperazinonesthus produced can then be reacted, for example, with a (1-, 2- or3-indoly1)-lowe-ralkyl halide according to the procedure of Method Aabove the resulting l-[(l-, 2,- and3indolyl)loweralltyl]-4-substituted-3-piperazinone or 1-[(1-, 2- and 3-indolyl) lower alkyl] 4 substituted 5 homopi- 13 perazinone reacted withan alkali metal aluminum hydried to produce the 1-[(l-, 2- or3-indolyl)-lower-alkyl]- 4-substituted-piperazines or l-[(1-, 2- or3-indolyl)-loweralkyl]-4-substituted-homopiperazines of Formulae la, band 0.

Method A was chosen above for purposes of illustration only but it is tobe understood that Methods B, C. D and E can be adapted to theabove-described synthesis as well. That is, it is only necessary tosubstitute for the l-substituted-piperazine and thel-substitutedhomopiperazine used in Methods A, B, D and E or the4-substituted-l-piperazinyl-lower-alkanoyl halide and 4-substituted-l-hornopiperazinyl-lower-alkanoyl halide used in Method Cthe corresponding l-substituted-Z-piperazinones andl-substituted-7-homopiperazinones or the l-(4-substituted-3-piperazinonyl)-lower-alkanoyl halide and l (4 substituted5 homopiperazinonyl) loweralkanoyl halide, respectively, and proceed asdescribed above. Thus in addition to the l-[(1-, 2- and 3-indolyl)-lower-alkyl]-4-substituted-3-piperazinones and 1-[(l-, 2- and 3-indolyl)-loWer-alkyl] -4-substituted-5-homopiperazinones afforded by Method A,there can also be ob tained l-[(3-indolyl) glyoxalyl] 4 substituted -3piperazinones and l [(3 indolyl)glyoxalyl]-4-substituted-5-homopiperazines by Method B, 1- [w- (3-indolyl)-e=- keto lower alkyl] 4substituted 3 piperazinones and l [w (3 indolyl) w keto lower alkyl] 4substituted-S-homopiperazinones by Method C, l-[l-, 2- or3-indolyl)-ot-lceto-loWer-alkyl]-4-substituted 3 piperazinones andl-[(1-, 2- or 3-indolyl)-a-keto-loWer-alkyl]-4-substituted-5-homopiperazinones by Method D and l- [(3 indolyl)methyl] 4 substituted 3 piperazinones, 1- (3-indolyl) methyl]-4-substituted-5-homopiper azinones by Method E. These on reaction withan alkali metal aluminum hydride afford, as the case may be, either thel-[(1-, 2- and 3-indolyl)-lower-alkyl]-4-substitutediperazines, 1-[(l-,2- and Z-indolyl)-lower-alkyl]-4-substituted-homopiperazines, 1[w-(3-indolyl) w hydroxylower-alkyl]-4-substituted-piperazines or thel-[w-(3- indolyl) w hydroxy lower-alkyl]-4-substituted-homopiperazinesof Formulae la. b and c.

An alternative procedure for the preparation of the 1-,substituted-7-homopiperazinones of Formula XV that are obtained when a,B-halo-lower-alkanoyl halide is reacted with an ethylenediamine ofFormula XH (m is 1) comprises reacting a l-substituted-4-piperidone withhydrazoic acid in the presence of a strong mineral acid, for examplesulfuric acid, phosphoric acid or hydrochloric acid, and a in anappropriate organic solvent inert under the conditions of the reaction,for example benzene, chloroform, trichloroethylene and the like. Thehydrazoic acid can be in the form of a solution of hydrazoic acid in thesolvent used or, if desired, in the form of an alkali metal salt, forexample sodium azide. In the latter case, the alkali metal salt reactswith the mineral acid used to produce the hydrazoic acid in situ. Thereaction is preferably carried out at a temperature in the range fromabout l0 C. to 25 C. Preferred solvents are benzene and chloroform and apreferred acid is sulfuric acid.

' The method is particularly preferred for the preparation of1-substituted-homopiperazinones corresponding to Formula XV where R andR are both hydrogen atoms. However, l-substituted-homopiperazinoneswhere R and R are both the same lower-alkyl radical are also preparedadvantageously by this method from symmetrical1-substituted-di-lowcr-alkyl-4-piperidones, such as 1-substituted-2,6-di-lower *alkyl-4-piperidones orl-substituted-3,5,-di-lower-alkyl-4-piperidones, since the racernicmixture of l-substituted-di-lower-alkyl 5 homopiperazinones produced inthe reaction give, on reduction with an alkali metal aluminum hydride, aracemic mixture of the same 1-substituted-di-loWer-alkyl-homopiperazine.On the other hand, when l-substituted mono-lower-alkyl-4- piperidones orunsymmetrical 1-substituted-di-lower-alkyl-' 4-piperidones are employed,for example a l-substituted- 2,5-di-lower-alkylt-piperidone, the mixtureof products,

on reduction with an alkali metal aluminum hydride, give isomeric1-substituted-homopiperazines and thus necessitate a separation of theisomers before proceeding to the next step.

The compounds of my invention are useful in the free base form or in theform of acid-addition or quaternary ammonium salts, and both forms areWithin the purview of the invention, and, in fact, are considered to beone and the same invention. The acid-addition and quaternary ammoniumsalts are simply a more convenient form for use, and in practice, use ofthe salt form inherently amounts to use of the base form. As used in theappended claims, unless specifically designated otherwise, the termsl-[(l-, 2- or 3-indolyl)-lower-alkyl]piperazine or4-substituted-piperazine, 1-[(l-, 2- or3-indolyl)-lower-alkyl]homopiperazine or 4 substitutedhomopiperazine,l-[w-(3-indolyl] w hydroxy-loweralkylJ-pipcrazine or4-substituted-piperazine, or 1- [w-(3-indolyl) whydroxy-lower-alkyl]homopiperazine or 4-substituted-homopiperazine meansboth the free base form and the acid-addition and lower-alkyl,loweralkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammoniumsalt form of the molecular structure recited. Pharmacologicallyacceptable salts are salts whose anions are innocuous to the animalorganism in pharmacodynamic doses of the salts, so that beneficialphysiological properties inherent in the free bases are not vitiated byside-effects ascribable to the anions; in other words, the latter do notsubstantially affect the pharmacological properties inherent in thecations. Appropriate acidaddition salts are those derived from mineralacids such as hydrochloric acid, hydrobrornic acid, hydriodic acid,nitric acid, sulfuric acid and phosphoric acid; and organic acids suchas acetic acid, citric acid, lactic acid,-

tartaric acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, sulfamic acid and quinic acid. The quaternaryammonium salts are obtained by the addi tion of esters having a'molecular weight less than about 250 to the free base form of thecompounds. A preferred class of esters comprises lower-alkyl,lower-alkenyl or monocarbocyclic aryl-lower-alkyl esters of inorganicacids or organic sulfonic acids having a molecular weight less thanabout 250. The lower-alkyl and lower-alkenyl esters can contain from oneto about four carbon atoms, and the monocarbocyclic aryl-lower-alkylesters can contain from seven to about ten carbon atoms. The estersinclude such compounds, inter alia, as methyl chloride, methyl bromide,methyl iodide, ethyl bromide, propyl chloride, Z-hydroxyethyl bromide,allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate,methyl p-toluenesulfonate, benzyl chloride, benzyl bromide, andsubstituted benzyl halides, such as p-chlorobenzyl chloride,p-nitrobenzyl chloride, o-chlorobenzyl chloride, pmethoxybenzylchloride, and the like.

The acid-addition salts are prepared either bydissolvr ing the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an orgarlic solvent, in which case the salt separates directly or:

can be obtained by concentration of the solution.

The quar-ternary ammonium salts are prepared by mixquaternary ammoniumsalt separates directly or can be obtained by concentration of thesolution.

Although therapeutically acceptable salts are preferred,

those having toxic anions are also useful. All acid-addition salts areuseful as intermediates in purification of the free bases, and toxicacid-addition and quaternary ammonium salts are useful as intermediatesin preparing therapeutically acceptable salts by ion exchangeprocedures.

Pharmacological evaluation of the compounds of the invention hasdemonstrated that they possess a variety of depressant actions on thecentral and autonomic nervous system, the cardiovascular system and theskeletalmuscular system. They lower the blood pressure; they decreasethe incidence of vomiting induced by apomorphine; they lower the rectaltemperature; they potentiate the sleeping time induced by ether,thiopental sodium or hexobarbital sodium; and they producetranquilization and skeletal muscle relaxation. These results indicatetheir usefulness as hypotensive agents, antinauseants, antipyretics,sedatives, tranquilizers and skeletal muscle relaxants. The compoundscan be prepared for use by dissolving under sterile conditions a saltform of the compounds in water (or an equivalent amount of a nontoxicacid if the free base is used), or in a physiologically compatibleaqueous medium such as saline, and stored in ampules for intramuscularinjection. Alternatively, they can be incorporated in tablet or capsuleform for oral administration. They are formulated and used in the sameway as known compounds having similar activities, such aschlorpromazine. The toxicity of the compounds of the invention is of thesame order of magnitude as that of chlorpromazine.

The structures of the compounds of the invention have been establishedby the mode of synthesis and corroborated by chemical analysis.

The following examples will further illustrate the invention without thelatter being limited thereto.

PREPARATION OF INTERMEDIATES Example 1 1-[2- S-indolyl) ethyl]-4-rnethyl-2-piperazinone benzochloride [Xa; R R R R and R are H, R isCH C H is CH CH m is 1, Halis Cl-]: A solution of 11.5 g. (0.07 mole) ofN-benzyl-N-methyl-aminoethylamine in 20 ml. of tetrahydrofuran was addedover a five minute period with stirring to a solution of 14.6 g. (0.07mole) of 3-indoleglyoxalyl chloride in 100 ml. of tetrahydrofuran. Themixture, which had become quite warm, was allowed to stand for about ahalf hour. About one liter of water and one equivalent of aqueous sodiumhydroxide were added, and the product which separated was collected andrecrystallized twice from ethanol giving 9.7 g. ofN-benzyl-N'-(3-indolyl)glyoxalyl-N-methylethylenediamine, M.P. 124.5127C. (uncorr.) [Corresponds to VIIIa; R R R and R are H, R is CH m is 1,and C 1H2 2 iS Twenty-six grams (0.078 mole) of the N-benzyl-N'-(3-indolyl)glyoxalyl-N-methylethylenediamine dissolved in 125 ml. oftetrahydrofuran were added to a stirred suspension of 19 g. (0.05 mole)of lithium aluminum hydride in 250 ml. of tetrahydrofuran. The greenishmixture was refluxed and stirred for seven hours and then allowed tostand overnight at room temperature. A solution of 25 ml. of water and75 ml. of tetrahydrofuran was added with stirring over a period of twoand a half hours. An additional 30 ml. of water was added, the mixturewas stirred for one hour, and 250 ml. of methylene dichloride was addedand stirring continued for another half hour. The reaction mixture wasfiltered, the filter was washed with methylene dichloride, and thefiltrate dried over magnesium sulfate and taken to dryness giving alight brown oil. The oil was crystallized from ethyl acetate giving 15.0g. of N-benzyl-N'[2-(3-indolyl)ethyl]-N- methylethylenediamine, M.P.102-105 C. (uncorr.). [IXa; R R R and R are H, R is CH n is 2, m is 1].

A solution of 10.13 g. (0.033 mole) of the N-benzyl-N'-[2-(3-indolyl)ethyl]-N-methylethylenediamine, prepared above, in 60 ml.of methylene dichloride was stirred and cooled while adding a solutionof 4.07 g. (0.036 mole) 15 of u-chloroacetyl chloride in 15 ml. ofmethylene dichloride over a period of forty minutes. The mixture wasallowed to stand at room temperature for an hour and a half, thenrefluxed for one hour and cooled. A little water and one equivalent ofdilute sodium hydroxide were added, the mixture was stirred for fifteenminutes and then filtered giving a first crop of 3.6 g. of product, M.P.229.5- 232.5 C. (uncorr.). The methylene dichloride layer was separatedfrom the filtrate and the aqueous layer extracted once with methylenedichloride. The combined organic extracts were dried and evaporated andthe residue recrystallized once from methanol giving an additional 1.8g. The combined samples gave 5.4 g. of 1-[2-(3- indolyl)ethyl]-4-methyl2 piperazinone benzochloride, M.P. 226.6-228.6 C. (corr.).

Analysis.Calcd. for C H CIN O: C, 68.82; H, 6.83; N, 10.95. Found: C,68.70; H, 6.78; N, 10.93.

Example 2 1-[2-(3-indolyl) ethyl] -4-rnethyl-2 piperazinone [XIa; R1,R3, R4, R5 and-R are H, R2 is CH3, C C is CHZSHQ, m is 1]: By reducingthe 1-[2-(3-indolyl)ethyl]-4-methyl- 2-piperazinone benzochlorideprepared above in Example 1 over 10% palladium-on-charcoal in an ethanolor Cellosolve solution and isolating the product from an alkalinemedium, there can be obtained 1-[2-(3-indolyl)ethyl]-4-methyl-2-piperazinone.

Example 3 N-benzyl-N'-[2-(3-indolyl)ethyl] N phenylethylenediaminedihydrochloride [1Xa; R R R and R are H, R is C H n is 2, m is 1], wasprepared from 27 g. (0.13 mole) of 3-indolegyloxalyl chloride and 58 g.(0.26 mole) of N-benzyl-N-phenylaminoethylamine in 300 ml. oftetrahydrofuran according to the manipulative procedure described abovein Example 1. There was thus obtained 41.9 g. ofN-benzyl-N'-(3-indolyl)glyoxalyl-N-phenylethylenediamine, M.P.162.2162.8 C. (corr.).

Analysis.Calcd. for C H N O N 10.57; N 3.52. Found: N 10.38, N 3.61.

The above glyoxamide (103 g.,'0.26 mole) was reduced with 76 g. (2.0moles) of lithium aluminum hydride in 2.2 liters of tetrahydrofuranaccording to the manipulative procedure described above in Example 1.There was thus obtained 64 g. of N-benzyl-N'-[2-(3-indolyl)ethyl]-N-phenylethylenediarnine dihydrochloride, M.P. 171.4 175.4 C. (corr.).

Analysis.Calcd. for C H N 2HC1: N, 9.50, Cl, 16.03. Found: N, 9.25; CI,16.12.

Example 4 Example 5 1-[2-(3-indolyl)ethyl]-4,6-dimethyl 2 piperazinoneR1, R3, R4, and R5 are H, R2 iS CH3, R6 is 6-CH3, C H is CH CH m is 1]:By followingthe manipulative procedure described above in Examples 1 and2 and by replacing the N-benzyl-N-methyl-aminoethylamine used thereinwith a molar equivalent amount of l-(N-benzyl-N-methylamino)-2-propylamine, there can be obtained 1- [2-( 3-indo1yl)ethyl] -4,6-dimethyl-2-piperazinone.

17 Example 6 1-[2-(3-indolyl)ethyl] -3-isopropyl-4-methyl2 piperazinone[XIa; R R R and R are H, R is CH R is 3-CH(CH C H- is CH CH- m is 1]:the manipulative procedure described above in Examples 1 and 2 and byreplacing the a-chlorocacetyl chloride used therein with a molarequivalent amount of a-ChlOIO- isovaleryl chloride, there can beobtained 1-[2-(3-indolyl) ethyl] -3-isopropyl-4-methyl-2-piperazinone.

Example 7 l [2 (3 indolyl)ethyl] 2,5 dimethyl 7 homopiperazinone [XIa; RR R and R are H, R is CH R is 2-CH c m, is CH CH m is 2]: By followingthe manipulative procedures described above in Examples 1 and 2, and byreplacing the N-benzyl-N-methylaminoethylamine used therein with a molarequivalent amount of l-(N-benzyl-N-methylamino)-3-butylamine, there canbe obtained 1-[2-(3-indo1yl)ethyl]-2,5-dimethyl-7-homopiperazinone.

Example 8 1 [2 (3 indolyl)ethyl] 2,5,6 -trimethy1- 7 homopiperazinone[XIa; R R and R are H, R is CH R iS 6-CH3, R6 is 2'CH3, C H2 is CH2CH2,m is 2]: following the manipulative procedure described above inExamples 1 and 2, and by replacing the N-benzyl-N-methylaminoethylamineand the a-chloroacetyl chloride used therein with molar equivalentamounts of l-(N-benzyl-N- methylamino)-3-butylamine anda-chloropropionyl chloride, respectively, there can be obtained1-[2-(3-indolyl) ethyl] 2,5,6-trimethyl-7-homopiperazinone.

Example 9 1-pheny1-2-piperazinone [XV; R is C H R nd R are H, m is 1]:To a solution of 177 g. (0.5 mole) of 1- (N,N-dibenzylamino) 2(N'-phenyl)ethylamine in 650 ml. of chloroform was added 80 ml. (120 g.,1.0 mole) of a-chloroacetyl chloride. The resulting red solution wasrefluxed for five and a half hours. The solvent and the bulk of theexcess acid chloride were removed in vacuo and the residue dissolved inchloroform once again and extracted with dilute sodium hydroxide. Theorganic extracts were dried and the solvent removed leaving 190 g. ofcrude 1-(N,N-dibenzylamino)-2-(N'-a-chloroacetyl-. N-phenyl)ethylamine.The oil was taken into hot cellosolve and the solution refluxed for fourhours. The cooled solution was diluted to a .volume of 650 ml. withabsolute ethanol. The resulting solution of 1-benzyl-4-phenyl-3-piperazinone benzochloride was divided into two portions andeach reduced over 2 g. of 10% palladiumon-charcoal under 50 p.s.i. of.hydrogen. Reduction in each case was essentially complete in about sixhours. The solutions were combined and treated with excess alcoholichydrochloric acid and diluted strongly with ether. The resulting solidwhich separated was collected and dried giving 91 g. of crudel-phenyl-Z-piperazinone hydrochloride. The hydrochloride saltiwasconverted to the free base by treatment with alkali and the crude basesublimed at reduced pressure and recrystallized from ethyl acetategiving l-phenyl-Z-piperazinone, M.P. l105 C. (uncoriz).

Analysis.--Calcd. for C H N oz C, 68.15; H, 6.87; N, 15.90. Found: C,68.27; H, 7.07; N, 15.77.

A small amount of the base wasconverted to the ptoluenesulfonic acidsalt giving l-phenyl-Z-piperazinone p-toluenesulfonate, M.P. 220.2224.6C; (corn).

Analysis.Calcd. for C H N O.C H O S: N, 8.04; S, 9.20. Found: N, 8.01;S, 9.07. r

1-phenyl-2-piperazinone can be reacted with hydrobromic acid, hydriodicacid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citricacid, lactic acid, tartaric acid or p-toluenesulfonic acid to give thehydrobromide, hydriodide, nitrate, sulfate (or bisulfate), phosphate (oracid phosphate), acetate, citrate (or acid cit By following 18 rate),lactate, tartrate (or bitartrate or p-toluenesulfonate salts,respectively.

Example 10 l-(4-chlorophenyl)-2-piperazinone hydrochloride [XV; R is4-C1C H R and R are H, m is 1], was prepared from 38.7 g. (0.1 mole) ofN-(4-chlorophenyl)-N',N'- dibenzylethylenediamine and 22.5 g. (0.2 mole)of achloroacetyl chloride in chloroform according to the manipulativeprocedure described above in Example 9. There was thus obtained theintermediate 1-(N,N-dibenzylarnino) 2 [N"- (a-chloroacetyl N (4chlorophenyl)]ethylamine hydrochloride, M.P. 161.0l63.8 C. (corn).

Analysis.Calcd. for C H Cl N OHCl: N, 6.04; Cl, 22.93. Found: N, 5.94;Cl,- 22.90.

The latter was converted to the free base, quaternized in boilingCellosolve and the resulting quaternary salt debenzylated over apalladium-on-charcoal catalyst according to the manipulative proceduredescribed above. in Example 9. There was thus obtainedl-(4-chlorophenyl)-2-piperazinone hydrochloride, M.P. 192.8-194.8 C.(corr.).

Analysis.-Calcd. for C H ClN O.HCl: C, 48.60; H, 4.90; N, 11.34. Found:C, 48.37; H, 5.10; N, 11.05.

Example 11 1 (2,6-dimetbylphenyl) -2-piperazinone hydrochloride [XV; Ris- 2,6-(CH C H R and R are H, m is l], was prepared from 68.8 g. (0.2mole) of 1-(N,N-dibenzylarnino) 2 [N' (2,6 dimethylphenyHethylamine and45 g. (0.4 mole) of u-chloroacetyl chloride in 300 ml. of chloroformaccording to the manipulative procedure described above in Example 9.Catalytic debenzylation of the quaternary ammonium salt was interruptedafter the uptake of one mole of hydrogen, and there was thus obtainedthe intermediate 4-benzyll-(2,6-dimethylphenyl)-2-piperazinonehydrochloride, M.P. 248.8264.8 C. (corn).

Analysis.Calcd. forC H N QHClz 8.47. Found: Cl, 10.58; N, 8.50.

On continued reduction of the above 4-benzyl-1-(2,6-dimethylphenyl)-2-piperazinone hydrochloride over pal-vladium-on-charcoal, there was obtained 1-(2,6-dimethylphenyl)-2-piperazinone hydrochloride, M.P. 224.8-2260" C. (corn).

Analysis.Calcd. for CmHmNgO-HCIJ Cl, N, 11.64. Found: Cl, 14.66; N,11.54.

Example 12 1-phenyl-6-methyl-2-piperazinone [XV; R is C H R is H, R is6-CH m is 1]: By following the manipulative procedure described above inExample 9 and by replacing the 1-(N,N-dibenzylamino)-2(N'-phenyl)ethylamine used therein with a molar'equivalent amount of 1(N,N dibenzylamino) 2' (N phenyl)propylamine, there can be obtained1-phenyl-6methyl-2-piperazinone.

" Example 13 1-phenyl-3-isopropyl-2piperazinone [XV; R is C H R is3-CH(CH R is H, m is 1]: By following the manipulative proceduredescribed above in Example '9 and by replacing the a-chloroacetylchloride used therein with a molar equivalent amount ofa-chloroisovaleryl chloride, there can be obtained1-phenyl-3-isopropyl-2- piperazinone.

' Example 14 1-phenyl-3-methyl-7-homopiperazinone [XV; R is C H R is H,R is 3-CH m is 2]: 'By following the manipulative procedure describedabove in Example 9 and by replacing the 1-(N,N-dibenzylamino)-2-(N'-phenyl)ethylamine used therein with a molar equivalent amount of2-(N,N-dibenzylamino)-4 (N'-phenyl)butylamine, there can be obtained1-phenyl-3-methyl-7-homo-. piperazinone. i t

1 9 Example 1-phenyl-3,6-dimethyl-7-hornopiperazinone [XV; R is C H R is6-CH R is 3-CH m is 2]: By following the manipulative proceduredescribed above in Example 9 and by replacement of the1-(N,N-dibenzylamino)-2- (N'-phenyl)ethylamine and the a-chloroacetylchloride used therein by molar equivalent amounts of 2-(N,N-dibenzylarnino)-4-(N-phenyl)butylamir1e and tit-chloropropionylchloride, respectively, there can be obtained *1-phenyl-3,6-dimethyl-7-homopiperazinone.

Example 16 1 [2 (3 indolyl)ethyl] 4 phenyl 3 piperazinone [XVIa; R R R Rand R are H, R is C H C H- is CH CH m is 1]: .A solution of 3.52 g.(0.02 mole) of the 1-pheny1-2-piperazinone prepared above in Example 9,5.0 g. (0.02 mole) of 2-(3-ind0lyl)ethyl bro mide and 2.8 g. (0.02 mole)of anhydrous potassium carbonate in 30 ml. of acetonitrile was refluxedfor five hours, then cooled, diluted with water and basified with dilutesodium hydroxide. The mixture was extracted with chloroform and theextracts dried and evaporated. The residual brown gummy material wasrecrystallized twice from methanol giving 2.4 g. of 1-[2-(3-indolyl)ethyl]-4-phenyl-3piperazinone, M.P. 163.2164.4 C. (corr).

Analysis.Calcd. for C H N O: C, 75.21; H, 6.63; N, 13.16. Found: C,75.32; H, 6.56; N, 13.06.

Examples 17 22 TABLE 1 (FORMULA XVIa) Example R R B6 In 17 4-C1CA'FT:'FT H 1 18 2,6-(CH2):CH3 H 1 1n CAH' H 1 20 C0H5 1 21 C5H5.. 2 22 C51152 Example 23 1 [(3 indo1yl)glyoxalyl] 4 (2 methylphenyl) piperazine[IVa; R R R R and R are H, R is 2-CH C H m is 1]: A cold, stirredsolution of 79.2 g. (0.45. mole) of 1-(2-methylphenyl)-piperazine in 500ml. of tetrahydrofuran was treated all at once with 31.2 g. (0.15 mole)of (3-indolyl)glyoxalyl chloride. There was an immediate voluminous.precipitate of a white crystalline solid which was removed byfiltration. The filtrate was taken to dryness and the residual lightbrown gum was stirred and shaken with about 700 ml. of water, 120 ml. ofethyl acetate and about 25 ml. of acetic acid. The mixture was warmed ona steam bath and the resulting solid was collected after cooling in anice bath thus affording 4 1.5 g. (80%) of 1-[(3-indolyl)glyoxalyl]-4-(2-methylphenyl) piperazine as a near white solid.

Examples 24-91 By following the manipulative procedure described abovein Example 23, substituting for the reactants used therein anappropriate (3-indolyl)glyoxalyl chloride and l-substituted piperazine,there were obtained, the compounds of Formula IVa listed below in Table2 where R and R in each is H and m in each is 1. The melting points areuncorrected unless noted otherwise and in the columns headed Analysis,"the symbols N and N represent total nitrogen and basic nitrogen,respectively.

TABLE 2 (FORMULA Wu) 33... ecH-.

4-CH3C5H1 34-." 6-CH3O;

3 25 2011300111. i 205 j gg fi H 148-55 3 B 4 37--- 5CBH5CH20. FT 13540CHCH on H as.-. s cri s 2 2 H 188% {0,66.46--- 0.66.80. i 36 5 21 ir'gsfi'fl 1115. 13.

N 10 70." N 10.79. {NB,a5s. Nia,6.59.

2124s 200.4- {N13 10.74.. NT, 10.50. 78.4 NB,3.58- NB,3.59. 44-..5,5-oorno H 2054,

{021952 1 01, 22- H H 211-5 g 231-8 Ti 40.-- 50411-01130... H..-.-

2 onaoofirr, 218 22 sear-012130 H P H 4 {NT,9.92- NT, 9.86. 45 51 2 1 1925151. NB,3.31-- 103,322.

1- a 2 8-36 4-GH 00H- 52..- sedfongoi N 9.56---- N, 9.43.

173-266 maths {N13 10.95" 1 0 7 4 55 215-22 F }155 (dee) 0,03,39.-.0.53.10. 125. 2-8. a H, 5.07 H, 4.77. ,1 0.54 N, 10.50 214-10 C1,8.8901,0.54 3CH3OCGH 211-13 ,1o.49 N, 10.14 71 G-CHaO 18H 79 E-CiIIhOC IL -w-1 1i 2,0- oH, 2om. 215-8 TABLE 2 (FORMULA IVa)-Continued Analysis Ex.R1/R2 Ra/R4 M.P., C.

Calcd. Found 73... G-CHaO H"-.-

2033050106113" 208 11 N, 9.s2 N, 9.75. 74--- 5,6-d1-CH30 H 210.2-{NT,1o.31 NT,10.07.

051150112 H 11.8 N11,3.44- Nn,3.37. 75--- gtg so-fi-cutou H NT,14.21NT,1a.9s 172. 5-3.5 NT,11.56 NT, 11.31

NT 9.61--- NT, 9.71 20113006111 {N15, 3.20-- N11, 3.13

5 a 1 so--- 56-dl-CH3O 01511-. 81 g gg gg g H 119-22 NT, 10.68-. NT,10.82

3 82 grggtgga H 12H a s3 saggaggam il' 15963-5 N 997 N 996 2,e(om)2oH3H--- {N13, 3.32-- NB, 3.50 84... 5,6-OOH1 0113" 23% 243113005114--. H85... 5 10131120.... Hum H 85 b li ii g a l l l l l eta-ease a 2 s 89HCHSOCSHLH 162 165.5

2242-511 oa s- 90... H

0611513112..- 174-4456 {N13,4.o3 NB,4.01 91--- 5,6-di-OH O H 214.0 1%,9.82-.- NT, 9.81 20105114 H---" Indei'. NB,3.27 NB,3.34

Corrected.

Examples 92-4 04 By following the manipulative procedure described abovein Example 23 and by substituting for the reactants used therein anappropriate (3-indolyl)glyoxa1yl chloride and l-substituted piperazine,there can be obtained the compounds of Formula lVa listed below in Table3 where R R and R in each is H and m in each is 1:

TABLE 3 (FORMULA No) :1)2 CHQCH (CH 2)s s Example 105 1 [3(5-chloro-3-indolyl)-3-keto-1-propyl]-4-benzhydrylpiperazine [Va; R is5-Cl, R is (C H CH, R R and R are H, C H is CH CH m is 1]: By reactionof l-benzhydryl piperazine with acrylonitrile in the presence of a basiccatalyst, for example Triton B, in an appropriate organic solvent, forexample ethanol, there can be obtained 5-(4-benzhydryl-l-piperazinyl)propionitrile. On hydrolysis of the latter in boiling aqueous sulfuricacid and isolating the product from a neutral medium, there can beobtained fi-(4-benzl1ydryl- 1-piperazinyl)propionic acid, which onreaction with thionyl chloride gives B-(4-benzl1ydryl-l-piperazinyl)propionyl chloride. On addition of the latter to a cold ether ortetrahydrofuran solution of S-chloroindolyl magnesium bromide (preparedby reaction of S-chloroindole with an ether solution of, for example,ethyl magnesium 22 bromide), there can be obtained1-[3-(5-chloro-3-indolyl) -3-ketol-propyl] -4-benzhydrylpiperazine.

Example 106 1 [3(S-chloro-l-rnethyl-S-indolyl)-3-keto-1-propyl]-4-benzhydrylpiperazine[VIa; R is 5-01, R is (C6H5)2CH, R3, R5 and R6 are H, R4 is CH3, C 1H2 2is CH CH m is 1]: By adding the 1-[3-(5-chloro-3- indolyl)3-keto-1-propyl]-4-benzhydrylpiperazine prepared above in Example 105 toa'solution containing one molar equivalent of sodamide in liquid ammonia(prepared by dissolving one atom equivalent of sodium in liquid ammonia)and treating the resulting solution with one molar equivalent of amethyl halide, for example methyl iodide, there can be obtained 1-[3-(5-chloro 1 methyl-3-indolyl)-3-keto-1-propyl]-4-benzhydrylpiperazine.

Example 107 1-[4-(1-benzyl-2-phenyl-3-indolyl)-4-keto 1 butyl]-4-phenylpiperazine [VIa; R is H, R and R are C H R4 is C6H5CH2, R5 andR6 are H, C 1H2 2 is (CH2)3]I By reacting l-phenylpiperazine withacrylonitrile in the presence of a basic catalyst, for example Triton B,in an appropriate organic solvent, for example ethanol, there can beobtained fi-(4-phenyl-l-piperazinyl)propionitrile, On refluxing thelatter in anhydrous methanol saturated with hydrogen chloride, there canbe obtained methyl fi-(4-phenyl-1-piperazinyl)propionate. The latter onreduction with lithium aluminum hydride gives 3-(4-phenyl-l-piperazinyl)-1-propan0l which on reaction with phosphoroustribromide gives 3-(4-pheny1-1-piperazinyl)-1- bromopropane. By reactingthe latter with magnesium turnings in anhydrous ether, carbonating theresulting solution of the Grignard reagent and isolating the prod: notfrom a neutral medium, there can be obtained 'y-(4-phenyl-1-piperazinyl)butyric acid. Treatment of the butyric acid withthionyl chloride gives 'y-(4-phenyl-1- piperazinyl)butyryl chloride.Reaction of the latter with 2-phenylindolyl magnesium bromide preparedaccording to the manipulative procedure described above in Example 105gives 1 [4 (2 phenyl-S-indolyl)-4-keto-1- butyl]-4-phenylpiperazine. Byreacting the latter with benzyl chloride in the presence of sodamideaccording to the manipulative procedure described above in Example 106,there can be obtained 1-[4-(1-benzy1-2-phenyl-3-indolyl)-4-keto-1-butyl]-4-phenylpiperazine.

Examples 108-112 By following the manipulative procedures describedabove in Examples 105 and 106 substituting for the reactants used inExample 105 a 4-rnethyl-1-piperazinylbutyryl halide and an appropriateindolyl magnesium halide and substituting for the methyl halide used inExample 106 an appropriate lower-alkyl halide, monocarbocyclicaryl-lower-alkyl halide or monocarbocyclic aryllower-alkenyl halide,there can be obtained the compounds of Formula VIa listed below in Table4 Where R 111 each is CH R R and R in each are H, C H in each is (CH andm in each is 1: i

TABLE 4: (FORMUIXA VIa) 1-[2-(3-indolyl) 1 ketoethyl] 4 phenylpiperazine[VIIa; R R R R and R are H, R is C H n is 2, m is 1]: To a cold, stirredsolution of 22.5 g. (0.132 mole) of indole-3-acetic acid and 13.3 g.(0.132 mole) of triethylamine in 800 ml. of acetone was added 1=8.1'g.

(0.132 mole) of isobutyl chloroformate and the solution was stirred atC. for twenty minutes. A solution of 21.4 g. (0.132 mole) ofl-phenyl-piperazine in a little acetone was added, and the solutionstirred for an hour and forty-five minutes at room temperature. I Theinsoluble material was removed by filtration, the filtrate taken todryness, and the residue redissolved in methylene di Chloride and washedwith water and dilute sodium hydroxide. The organic layer was dried, thesolvent removed and the residue recrystallized from ethanol giving 5.4g. of l-[2-(3- indolyl)-1-ketoethyl]-4-pheuylpiperazine, M.P. 179.4181.6C. (corr.).

Analysis.Calcd. for C H N3O: N 13.16; N 4.39. Found: N 12.91; N 4.39.

Example 114 Example 115 1-[3-(l-indolyl)-l-ketopropyl] 4phenylpiperazine [VIIc; R R R and R are H, R is C H C H is CH CH m isl], was prepared from g. (0.132 mole) of indole-l-propionic acid, 13.3g. (0.132 mole) of triethylamine, 18.1 g. (0.132 mole) of isobutylchloroformate and 21. .4 g. (0.132 mole) of l-phenylpiperazine in 800ml. of acetone according to the manipulative procedure described abovein Example 113. There was thus obtained 37 g. of1-[3-(l-indolyl-l-ketopropyl]-4-phenylpiperazine as a light brown oil.

Examples 116-126 By following the manipulative procedure described abovein Example 113, substituting for the reactants used therein anappropriate. 3-indole-lower-alkanoic acid and 1-substituted-piperazine,there were obtained the compounds of Formula VIIa listed below in Table5 in which R R R and R in each are hydrogen and m in each ing themanipulative procedure described above in Example 113, replacing theindole-3-acetic acid used therein with a molar equivalent amount ofindole-2-carboxylic acid, there can be obtainedl-(2-indolylcarbonyl)-4-pl1enylpiperazine.

Example 128 1-(3-indo'lylcarbonyl)-4-phenylpiperazine [VIIa; R R R R andR are H, R is C n is 1, m is 1]: By following the manipulative proceduredescribed above in Example 113, replacing the indole-3-acetic acid usedtherein with a molar equivalent amount of indole-3-carboxylic acid,there can be obtained 1-(3-indolylcarbonyl)-4-phenylpiperazine.

Examples 129-137 TABLE 6 (FORMULA VIIa) PREPARATION OF FINAL PRODUCTSExample 138 1-[2-(3-indolyl)ethyl]-4-phenylpiperazine [Ia; R R R R R andX are H, R is C H n is 2, m is 1]: A mixture of 5.6 g. (0.025 mole) of3-indolylethyl bromide, 4.1 g. (0.025 mole) of l-phenylpiperazine and2.1 g. (0.025 mole) of sodium bicarbonate in 30 ml. of absolute ethanolwas refluxed with stirring for six hours. The bulk of the solvent wasremoved in vacuo, water was added along with sufficient dilute sodiumhydroxide to render the 1 Corrected.

Example 127 1-(2-indolylcarbonyl)-4-phenylpiperazine [VIIb; R R

is 1, Th melting oint are uncorrected unless t d 50 mixture alkaline,and the mixture was extracted with otherwise. ether. The organicextracts were dried, the solvent re- TABLE 5 (FORMULA VIIa) AnalysisExample R1 R2 C -lHZn-Z M.P., C.

Calcd. Found 116 H 34311300 11 0W 117 H 2-C1C6HA 011 011 1 8 H 2-CHaCa 4CHzCH:i ufihfigun -fi 1 1 6 l T, T, 119 H Z'GHBOCUH; 01120112-.-.,173.0-10 120 H- cm. 121 H Z-CHaOCeHq 122 H s-cHaool-ai 123 6 CH30 C6115CHQCHZH 124 sol-I30 24111300111, 011 011 125 5,6-di-OH3O- 343100114 on126 5,6-OCH20 C5115 0112013 moved and the residue recrystallized fromacetone to give 1.4 g. of l-[2-(3-indolyl)ethyl]-4-phenylpiperazine,

R and R are H, R is C H n is l, m is 1]: By follow 75 M.P. 13l.6l36.0 C.(corn).

Analysis.Calcd. for C H- N C, 78.65; H, 7.59; N, 13.76. Found: C, 78.74;H, 7.74; N, 13.59.

Examples 139-142 By following the manipulative procedure described abovein Example 138 substituting for the reactants used therein anappropriate (3-indolyl)-lower-alkyl bromide andl-substituted-piperazine, there were obtained the (3-indolyl)-lower-alkyl-4-substituted piperazines of Formula Ia listedbelow in Table 7, where R R R R and X Example 159 1[2-(3-indolyljethyl]-4-(2-methylphenyl)piperazine in each is H, n ineach is 2 and m in each is 1. All [111; R R R R R and X are H, R is 2-CHC H melting points are corrected. n is 2, m is 1]: A solution of 41.5 g.(0.12 mole) of 1- TABLE7(FORMULA Ia) Analysis Example R I R: M.P., O.

Calcd. Found 0,7068--- 0,7030. m T-l' 401cm. 185. 2486.8 H, 6.52 H,6.51.

N, 12.37--- N, 12.23. 0,724.96--- 0, 78.62. 141--- H 401110 11 147.8-1548 H, 7.89---- H, 7.61.

N, 13.15--- N, 12.91. C, 75.61.-- 0,751.91. 141 s-cHaom 4011 11108.6l11.0 H, 7.79---- H, 7.88.

0,6602... 0, 65.57. 142 H C6H5CH=CHCHQ arise-263.6 H,6.99 H, 7.01.

Examples 143-147 By following the manipulative procedure described abovein Example 138, replacing the 3-indolylethyl bromide used therein with amolar equivalent amount of a (1-indolyl)-lower-alkyl halide and thel-phenylpiperazine used therein with a molar equivalent amount of anappropriate l-substituted-piperazine or 1-substituted-homopiperazine,there can be obtained the compounds of Formula Ic listed below in Table8 where R R and R in each is H.

TABLE 8 (FORMULA Ic) Examples 148-152 By following the manipulativeprocedure described TABLE 9 (FORMULA Ib) Examples 153-158 By followingthe manipulative procedure described above in Example 138 substitutingfor the reactants used therein an appropriate (3-indolyl)-loweralkylhalide and l-rnethylpiperazine, there can be obtained the 1'-[(3-in- Raa 011E211 11!.

4010151 11 Fl CH O'FIQ 1 2O5H4N CH3 CHzCH(CH3) 1 2-pyrimidyl C (CHzh 22-pyrazinyl C H (CH2); 2 2-thiazoly H (CH2 1 3-indolyl) -glyoxalyl] -4-(2-methylphenyl) piperazine in 250 m1. of tetrahydrofuran was added overa ten minute period to a stirred suspension of 2 7 g. (0.72 mole) oflithium aluminum hydride in 300 ml. of tetrahydrofuran. The mixture wasrefluxed and stirred for six and a half hours and the excess lithiumaluminum hydride then destroyed by the dropwise addition of 140 ml. ofsodium hydroxide solution. The mixture was filtered, the insolublematerial was washed with boiling chloroform, and the filtrate dried overanhydrous sodium sulfate and concentrated to dryness. The residual lightorange oil .Was crystallized from a benzene-hexane mixture giving 28.5g. of 1-[2-(3indolyl)ethyl]-4 (2-methylpheny1)piperazine, M.P.124.2l26.4 C. Y

Analysis.Calcd. for C H' N C, 78.96; H, 7.89; N, 13.16. Found: C, 79.05;H, 7.85; N, 13.10.

1 [2-(3-indolyl)ethyl]-4-(2-methylphenyl)piperazine can be reacted withhydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,phosphoric acid, acetic acid, citric acid, tartaric acid, quinic acid,methyl iodide, methyl bromide, ethyl bromide, allyl bromide, benz'ylchloride, .2-chlorobenzyl chloride or methyl p-toluenesulfonate to givethe hydrochloride, hydrobromide, hydriodide, sulfate (or bisulfate),phosphate (or acid phosphate), acetate, citrate (or acid citrate),tartrate (or bitartrat'e),

quinate, methiodide, vmethobromide, ethobromide, allobromide,benzochloride, 2-chlorobenzochloride, or methop-toluenesulfonate salts,respectively.

1 [2-(3-indolyl)ethyl]-4-(Z-methylphenyl)piperazine can be reacted witharsenic acid to give the arsenate salt which can be useful as acharacterizing derivative.

1 [2-(3-indolyl)ethyl]-4-(2-methylpheny1)piperazine, in the form of itshydrofiuoride salt can be converted to the hydrochloride salt by passingan aqueous solution of the former over an ion-exchange resin saturatedwith chloride ions, for example Rohm and Haas Amberlite IRA-400 resin.

Examples 160-224 By following the manipulative procedure described abovein Example 159, substituting for the 1-[(3-indolyl)dolyl)-lower-alkyl]-4-methylpiperazines of Formula Ia listed below inTable 10 where R R R R and X in each is H, R in each is CH and m in eachis l.

glyoxalyl]-4-(Z-methylphenyl)piperazine used therein the mula Ia listedbelow in Table 11 were prepared. All

melting points are corrected unless noted otherwise. In each example Rand R are H, n is -2 and m is 1.

3-indolyl)ethy1] 4 (4-methylphenyl)piperazine (1.8 g.,

TABLE 11 (FORMULA Ia)Continued (4-methylphenyl) piperazinemethanesulfonate, M.P. 233-235 C. (uncorr.).

The residual solid was recrystallized from ethanol to give1-['2-(5-hydroxy-3-indolyl) ethyl]-4-(4-methylphenyl)piperazine, M.P.193.2195.8 C. (corn).

I The latter was recrystallized from an acetonitrile-ethyl acetatemixture to give 0.004 mole) prepared above in Example 172 was dissolvedin 225 m1. absolute ethanol and reduced over 0.5

, X is CH, U is drogen. Reduction was complete in about three hours. Thesolution was filtered from the catalyst and the filtrate concentratedto'dryness.

Analysisr-Calcd. for C H N O: c, 75.19; H, 7.51; N. 12.53. Found: C,' 75.1 8;'H, 7.7 5; N, 12.16.

A small amount of the base was converted to the 1 [2(5-hydroxy-3-indolyl)ethyl-]-4 N, Found: 60 Analysis.- -Ca1cd. for C H NO S: N. 9.74 Found:

Example 225 Example 227 I[2-(5-hydr0xy-3ind0lyl)ethyl]-4-phenethylpipera- M.P. 193.2-198.0 and Xare H, n is 2, m is 1], was prepared from 1.9 g. (0.004 mole) of the 1-[2-(5-benzyloxy-3-indolyl)ethyl]- '4-phenethylpiperazine prepared abovein Example 173 according to the manipulative procedure described above70 in Example 226. The crude product was recrystallized ,from ethylacetate to give 1.4 g. of I-[Z-(S-hydroxy-Z- idolyl)ethyl]-4-phenethylpiperazine, V M.P. 1980-2016 C. (corn).

Example 226 Analysis.-Calcd. for C H N O: C, 75.61; H, 7.79;

d .O....7.6.. m amhaa daaraea aafifiaafifi mafi F s. nfl a mzmnnmz x a.m :LTB vBTB,, T TBTBTB w CNN HNNNCHCNCC N NNN I I I I a II I I ..I I mswa .mmm mmm ma e C .1 1 3 3 9 MM MNE n.7, 6 88 8 2 u L 3 m 2 1 0 2 Pmm" a .1. I I I I I I I I I I I I I I a I I I I. I I I I s I I I L m I II I C. I I I I a m H H- I I I a I I I II I I I I I I I I I I I I I x I II I I I Iv I I I I I I I I I I I hf Fu mim um mlhfmlmi hf II I I I I IIII II I 4 II I I I I I I E II I I I I I I .I IIIII III IIIIIIII FIE H HH HIHH EHIHWI HIImIImUImUIHH m I HIE II II III IIIIII I I IIII II IIIIII IIIIIIII I IIII I I II III III IIIIIIII I IIII III III IIIIIIII IIIII II III III IIIIIIII I IIII II III III IIIIIIII I III H II Im m. IoI IIIIII .ImIII R 4 I 0 H .2 1 a. .TIa LII a. a. a. a m ew ew a fifiamweomaaa a a IO 0 I0 I H HO H HMHMHC H0 o c osfic mc mm 0.0 0. H 00 w o mcm. 00. 00 oo 00 OH womwmacooo as ea ea also, soimem 9, 5 9 5 9 55 5 9.mzeaweameaea n p I I I I I I I I I I I I I I I I I I I I e I I I I I II I I I I I II. II I I I m I I I I I I I I I I I I I I I I I I I m I I II I I I I I I I I I I I I I I x I I I I I I I I I I I I I I I I I I E ILLS IZLLLLS I IL 2 a a m 2 mam a a m a ma mamwm 1 Uncorrected.

1-[2-(5,6-dimethoxy 3 7 indolyl)-2-hydroxyethyl]-4- y p y )T p 1 is a 2is g. of 10% palladium-on-charcoal under 51 p;s.i. of hy- 4-CH3C6H4, R3,R4, R5 and R6 are H AnalysiS.Calcd. for C23H29N302i N, 10.87. 4

The filtrate from the main crop on concentration afforded a second cropof 2.5 g. of crystals, M.P. 190-196 It was recrystallized from acetoneto give 2 g. of l-[2-(5,6-dimethoxy-3-indolyl)-2 hydroxyethyl]- 65 zine[161; R is S-HO, R is C H CH CH R R R R 4-(4-methylphenyl)piperazine, C(corn).

Analysl'S.CalCd. for C23H29N303: C, H, N, 10.63; 0, 12.14. Found: C70.04; H, 7.16; N, 10.55; 0, 12.08.

1 [2-(5-hydroxy-3-indo1yl)ethyl] -4-(4-methylphenyl) piperazine [Ia; Ris S-HO, R is 4-CH C H R R R R and X are H, n is 2, m is 1]: The1-[2-(5-benzyloxy- 75 N, 12.03. Found: C, 75.46; H, 7.63; N, 11.83.

m is 1], was isolated as a by-product in the preparation of1-[2-(5,6-dimethoxy-3-indolyl)ethyl] 4 (4-methylphenyl)piperazine(Example 184) from 33 g. (0.081 mole) of1-[(5,6-dimethoxy-3-indolyl)glyoxalyl]-4-(4- methylph'genyhpiperazineand 10 g. (0.263 mole) of lithium aluminum hydride in 1100 ml. oftetrahydrofuran according to the manipulative procedure described abovein Example 159. The crude product isolated from the e reaction mixturewas recrystallized from methanol to methane ulf i acid l give a firstcrop of 20 g. which on recrystallization from ethyl acetate gave 16.2'g. of 1-[2-(5,6-dimethoxy-3-indolyl)ethyl]-4-(4-methylphenyl)piperazine, MP. 134- 137 C. (uncorr.)(Example 184).

C. (uncom).

31 Example 228 1-[2-( 1-methyl-3 -indolyl)ethyl] -4-phenylpiperazine[Ia; R1, R3, R5,7-R6 and Xa-re H, R2 is CH5, R4 is CH3, 1: is 2, m is1]: To a stirred solution of 0.83 g. (0.036 atom) of sodium in 300 ml.of liquid ammonia under nitrogen was added 10.0 g. (0.033 mole) of1-[2-(3- indoly1)ethyl]-4-phenylpiperazine prepared above in Example138. The mixture was stirred for about one hour during which time theindole dissolved completely. To

the solution was then added a solution of 5.23 g. (0.036

mole) of methyl iodide in 100 ml. of ether and an additional 500 ml. ofliquid ammonia. The mixture was stirred for three hours and then allowedto stand at room temperature for two days. An additional 300 ml. ofether was addedand the unreacted sodamide destroyed by the addition of50 ml. of water. The organic layer was separated, dried over anhydroussodium sulfate and the solid that separated from the dried solutionwascollected and extracted with chloroform. The chloroform solution wasevaporated and the residual solid recrystaldioxy 3indolyl)ethyl]-4-(Z-methoxyphenyl)piperazine prepared above in Example220, 0.5 g. (0.022 atom) of sodium in 400 ml. of liquid ammonia and 4.5g. (0.026 mole) of benzyl bromide using the manipulative proceduredescribed above in Example 228. There was thus obtained 3.0 g. ofl-[2-(1-benzyl-2-methyl-5,6,- methylenedioxy 3 indolyDethyl]-4-(2-methoxyphenyl) piperazine, M.P. 169.2-170.2.C. (corr.).

Analysis.-Calcd. for C H N O 1 C, 79.51; H, 6.88; N, 8.69. Found: C,79.55; H, 6.71; N, 8.72.

Examples 231-243 By following the manipulative procedure described abovein Example 159 and by substituting for the l-[(3- indolyl)glyoxalyl] 4(2-rnethylphenyl)piperazine used therein the1-[(3-indolyl(glyoxalyl]-4-substituted-piperazine of Formula IVaprepared above in Examples 92-104 (Table 3 there can be obtained therespective compounds of Formula Ia listed below in Table 12 where R Rand R in each is H, n in each is 2 and m in each is 1:

TABLE 12 (FORMULA Ia) lized from methanol giving 4.7 g. of1-[2-(1-methyl-3- indolyl)ethyl]-4-phenylpiperazine, M.P. 93.8-95.6 C.(corn).

Analysis.-Calcd. fOl' C21H25N31 NT, NB, 8.78. Found: N 12.91; N 8.89.

Example 229 1 [2 (1,2 dimethyl-S,6-methylenedioxy-3-indolyl)ethyl]4-(2-methoxyphenyl)piperazine [lag R, is 5,6- OCHZO, R2 is2-CH3OC6H4, R3 and R4 are CH3, R5, R and X are H, n is 2, m is 1], wasprepared from 8.0 g. (0.020 mole) of 1-[2-(2-methyl-5,6-rnethylenedioxy-3 -indolyl) ethyl] -4-( 2-methoxyphenyl) piperazine prepared above inExample 220, 0.5 g. (0.022 atom) of sodium in 400 ml. of liquid ammonia,and 3.5 g. (0.024 mole) of methyl iodide using the manipulativeprocedure described above in Example 228. There was thus obtained 7.8 g.of 1 [2 (1,2-dimethyl-5,6-rnethylenedioxy-3-indolyl) ethyl] 4(Z-methoxyphenyl)piperazine, M.-P. 118.2- 119.6 C. (corr.).

Analysis.-Calcd. for C H N O C, 70.73; H, 7.17; N 6.77. Found: C, 70.93;H, 7.50; N 6.77.

Example 230 1 [2 (1 benzyl-2-methyl-5,6-methylenedioxy-3-indolyl)ethyl]-4-(2-methoxyphenyl)piperazine [Ia; R is 5,6-OCH20, R2 is2-CH3OC5H4, R3 is CH3, R4 iS C6H5CH2, R R and X are H, n is 2, m is 1],was prepared from 8.0 g. (0.020 mole) of 1-[2-(2-methyl-5,6-methylene-Example 244 1-[3-(5-chloro-3-indoly1) 1 propyl]-4-benzhydrylpiperazine[Ia; R is S-Cl, R is (C HQ CH, R R R R and X are H, C H is CH CH m is1]: By reacting the 1-[3-(5-chloro-3-indolyl)-3-keto-1-propyl]-4-benzhydrylpiperazine prepared above in Example with lithium aluminumhydride in an appropriate organic solvent, for example ether ortetrahydrofuran, according to the manipulative procedure described abovein Example 159, there can be obtained 1-[3-(5-chlor0-3-indolyl)-l-propyl] -4-benzhydrylpiperazine.

Example 245 Examples 246-252 By reacting the compounds prepared above inExamples 106-112 with lithium aluminum hydride according to themanipulative procedure described above in Example 105, there can beobtained the respective compounds 33 of Formula Ia listed below in Table13 where R and R in each is H, X in each is OH and m in eachis 1:

34 are H and m in each'is 1. The melting points are corrected unlessnoted otherwise.

TABLE 13 (FORMULA In) Example R1 R2 Ra/Rl Crr1H2n-2 (H9101{515.113:::::::::::::::::::::31:TA 247 H Gin. }(CH2)3 24s en-cimo H3}(CH2)3 249 aea-m-omo- 0H3 H2)a 250 FT 0m 2)s. 251 H' CH3 }(CH2): 252aeswmonmmorno CH3 Hi)i Example 2531-[2-(3-indoly1)ethyIJ-4-phenylpiperazine [lag R R R R R andX are H, Reis .C H n is 2, m. isl]: By reacting the 1-[2-(3-indolylll-ketoethyl]-4 phenylpiperazine obtained above in Example 113 withlithium aluminum hydride in an appropriate organic solvent; for exampleether or tetrahydrofuran, according to the manipulative proceduredescribed above in Example 159, there can be obtained1-[2-(3-ind0lyl)ethyl]-4-phenylpiperazine.

Example 254 1-[3-(3-indolyl)propyl]-4-phenylpiperazine [Ia; R R R R Rand X are H, R is C H C H is CH CH m is 1], was prepared from g. (0.060mole) of 1-[3-(3- indolyl) 1 ketopropyl] 4 phenylpiperazine, preparedabove in' Example 114, and 10.8 g. (0.360 mole) of lithium aluminumhydride in 600 m1. of tctrahydrofuran according to the manipulativeprocedure described above in Example 159. The crude product wasrecrystallized from absolute ethanol to give 10 g. of1-[3-(3-indolyl)propyl]- 4-phenylpiperazine, MP. 126.6-127.8 C. (corn).

Ana1ysis.Calcd. for C H N N 13.15; N 8.76. Found: N 13.11; N 8.50;

Example 255 1-[3-(1-ind0ly1)propyl]-4-phenylpiperazine [Ic; R R R5, R6and X are H, is C6H5, C 1H2 2 is m is 1], was prepared from 37 g. (0.111mole) of 1-[3- (l-indolyl)-1ketopropyl] 4 phenylpiperazine preparedabove in Example 115 and 16.9 g. (0.444 mole) of lithium aluminumhydride in one liter of tetrahydrofuran according to the manipulativeprocedure described above in Example 159. The crude product wasrecrystallized from methanol to give 19 g. of 1-[3-(1-indolyl)pr0pyl]-4-phenylpiperazine, M.P..96.7-98.4 C. (corn).

Analysis.-Calcd. for CZ1HZ5N3Z C, H,

' NB, 8.78. Found: c, 78.81; H, 7.65; N 8.47.

Examples 256-266 I By following the manipulative procedure describedabove in Example 2 54, substituting for the1-[3-(3-indolyl)-1-ketopropyl]-4-phenylpiperazine used therein. the1-[(3-indoly1) -a-keto-l0Wer-alky1] 4 -'substituted-piperazines preparedabove in Examples 116 to 126, there were obtained the respectivecompounds of Formula Ia listed below in Table 14 in which R R R R and Xin each l Hydrochloride salt.

Example 267 1-(Z-indolylmethyl)-4-phenylpiperazine [Ib; R R R R and Xare H, R is C H n is 1, m is 1]: By reacting the 1-(2-indolylcarbonyl) 4phenylpiperaziue prepared above in Example 127 with lithium aluminumhydride in an appropriate organic solvent, for example ether .,ortetrahydrofuran, according to the manipulative procedure described abovein Example 159, there can be lobtained1-(2-indolylmethyl)-4-phenylpiperazine.

' Examples 268-277 By reacting the compounds prepared above in Ex?amples 128-137 with lithium aluminum hydride in an appropriate organicsolvent, for example ether 'or tetrahydrofuran, according to themanipulative procedure described above in Example 159, there can beobtained the.

respective compounds of Formula Ia listed below in Table 15, where R R RR and X in each is H:

TABLE 15 (FORMULA Ia) Example R R: n m

26% W CrFf: 1 1 269 4-C2H5 C H5CH2CH2 2 l 270 5(CH3)2CH 4-CH3SCH4CH2CH22 1 271 6-CH3(CH2)4 4-(CH3)2CHSC5H4CH2OH2- 2 2 272 7-(CH )3O 3,4-0CHgOC5H3CHzCH2... 2 2 273 H Z-C5H4N 2 1 274 H Z-pyrirmdyl 2 2 2755,6-di-CH3O 2pyrazinyl 2 2 276 5.6-0 CHzO 2-thiazol 2 1 2775,6-OCH2CH20..- 2-(1,3,5-triazinyl) 2 1 35 7 Example 2781-(3-indolylmethyl)-4-phenylpiperazine [Ia; R R R R R and X are H, R isC H n and m are 1]: A solution of 6.25 ml. of formalin and 13.3 g.(0.082 mole) of l-phenylpiperazine in 100 ml. of dioxane was cooled to5-10 (1., and a solution of 9.0 g. (0.077 mole) of indole in 100 ml. ofdioxane was added with stirring over a period of about twenty minutes.When about half of the indole solution had been added, about 20 ml. ofglacial acetic acid was poured into the reaction mixture. The reactionmixture was allowed to stand at room temperature for about eighteenhours and then diluted with 400 ml. of water and extracted once withether. The aqueous layer was separated and basified with'aqueous sodiumhydroxide and extracted with ether. The organic extracts on drying andevaporating afiorded a yellow solid which was recrystallized fromethanol to give 7.0 g. of 1-(3-indolylmethyl) 4 phenylpiperazine, M.P.184.66.8 C. (corn).

Analysi.s'.-Calcd. for C H N N 14.42; N 4.81. Found: N 14.34; N 4.90.

Example 279 1-(5,6-dimethoxy-3-indolylmethyl 4 phenylpiperazine [101; R1is 5,6'di-CH30, R2 is C6H5, R3, R4, R5, R5 and X are H, m and n are l],was prepared from 5.0 g. (0.028 mole) of 5,6-dimethoxyindole, 4.9 g.(0.03 mole) of N-phenylpiperazine and 2.2 ml. of formalin and 5 cc. ofglacial acetic acid using the manipulative procedure described above inExample 278. The product was recrystallized from benzene giving 4.7 g.of l-(5,6-dimethoxy- 3-indolylmethyl)-4-phenylpiperazine, M.P.159.2l60.2 C. (corn).

Analysis.Calcd. for C H N O N 11.96; N 7.97. Found: N 11.36; N 7.76.

Examples 280-288 By following the manipulative procedure described abovein Example 278 and by replacing the l-phenylpiperazine used therein withan appropriate l-substitutedpiperazine or 1-substituted-homopiperazine,there can be obtained the compounds of Formula Ia listed below in Table16 where R R R R and X in each is H, and n in each is 1:

TABLE 16 (FORMULA la) l a 35 Example 2891-[2-(3-indolyl)ethyl]-4-methylpiperazine [Ia; R R R R R and X are H, Ris CH n is 2, m is 1]: By reacting the l- [2- 3-indolyl ethyl]-4-methyl-2-piperazinone prepared above in Example 2 with lithiumaluminum hydride in an appropriate organic solvent, for example ether ortetrahydrofuran, according to the manipulative procedure described abovein Example 159, there can be obtained 1-[2-(3-indolyl)ethyl]-4-rnethylpiperazine.

Examples 290-301 By reacting the compounds prepared above in Examples 4,5, 6, 7, 8, 16 and 17-22 with lithium aluminum hydride in an appropriateorganic'solvenhfor example ether or tetrahydrofuran, according to themanipulative procedure above in Example 159, there can be obtained therespective compounds of Formula Ia listed below in Table 17 where R Rand X in each is'H:

TABLE 17 (FORMULA Ia) 1-'{3-[2-(4-methylsulfinylphenyl) 3indolyl]-Z-ethylpropyl}-4-methylpiperazine [Iag R R R R and X are H, R2is CH3, R3 is 4-CH3SOC6H4, C 1H2 2 is CH(C H )CH m is 1]: By reactingthe l{3-[2-(4-methylmercaptophenyl)-3-indolyl]-2-ethylpropyl} 4methylpiperazine prepared above in Example 158 with one molar equivalentof peracetic acid (hydrogen peroxide dissolved in glacial acetic acid)in an appropriate organic solvent, for example ethanol, at a temperaturebetween about 0 C. and about 25 C., there can be obtainedl-{3-[2-(4-methylsulfinylphenyl)-3-indolyl]-2-ethylpropyl}-4methylpiperazlne.

Example R1 m Examples 3 03-31 0 (C H) CH 1 By following the manipulativeprocedure described a 2 2 above in Example 302, substituting for the1-{3-[2-(4- methylmercaptophenyl) 3 indolyl] 2 ethylpropyl} 4- 1methylpiperazine used therein the. compounds prepared above in Examples174, 175, 188, 235, 236, 248, 270 and z 2 271, there can be obtained therespective compounds of 20,3,Hr1azmy1) 2 Formula Ia listed below inTable 18 where R R and R are H and m in each is 1:

TABLE 18 (FORMULA Ia) Example R113; R4 X CMHIIH grgfg jiiiiiiijiijil CH15- 0- congealed" 305.----. 5,6di-OH3 4-CH3SOC5H4 CH! 306 G-CHaSOcmonacmcmomn CH2 307 gggggggei ;}+FcuH40H2-. on. 308 gfigffi}-4-CHaSOCaH4CH:CaH2- 011.). 209 5-CH. on- 3m g-gizgigtgilcmcm i H t me.efise'egmermmij H CH1 37 Example 311 1-{3-[2=(4-methylsulfonylphenyl)-3indolyl]-2' ethylpropyl} -4-methylpiperazine [111; R R R R and X are H,R2 is CH3, R3 is 4-CH3S02C6H4, C H2 2 is 38 The product wasrecrystallized from benzene giving 8.9 g. of1-[2-(5,6-dirnetl1oxy-3-indolyl)ethyl1piperazine, M.P. 109.6111.4 C.(corn).

Analysis.Calcd.' for C H N O N 14.5 2; N 9.68.

5 Found: N 14.32; N 9.45. 2 5) 2r Examples 322-325 m is 1]: By reactingthe 1-{3-[2-(4-methylmercapto- By following the manipulative proceduredescribed phenyl) -3-indolyl] -2-ethylpropyl} 4 methYIPIPeIaZiHe abovein Example 320, substituting for the 1- [2-(3-indolprepared above inExample 158 Wlth slightly more than 10 yl) ethyl]-4-'benzylpiperazineused therein the compounds two molar equivalents of peracetic acid(hydrogen peroirprepared above in Examples 239, 244, 245 and 246, thereide in glacial acetic acid) in an appropriate organic can be obtainedthe respective compounds of Formula Ia solvent, for example glacialacetic acid, at a temperature list d b l w in Table 20 where R R R and Ri h between about 20 C. and about 100 C., there can be i H and m i a h i1; obtained 1-{3-[2-(4-methylsulfonylphenyl) 3-indolyl]-2- TABLE(FORMULA Ia) ethyl-propyl}-4-methylpiperazine.

Examples 312-319 Example 7 R4 X By following the manipulative proceduredescribed 332 6-CHeO CaH5CHzCHz..--- OH... CH, above in Example 311substituting for the 1-{3-[2-(4- 20 2 3 g it I: methylmercaptophenyl) 3indoly1]-2-ethy1propy1}-4- 325 5-01 CH3- 0H--- onzyr methylpiperazineused therein the compounds prepared above in Examples 174, 175, 188,235, 236, 248, 270 The compounds of the invention when administered and271, there can be obtained the respective compounds orally to mice towhich 40 mg./ kg. of hexobarbital had of Formula Ia listed below inTable 19 where R R and 25 been administered produced potentiation ofhexobarbital- R in each is H and m in each is 1: induced sleeping time.They produced tranquilization'of TABLE 19 (FORMULA Ia) Example Ri/Rz R4X nl 2n2 :1 5-CH3SO'I }H H CH2 313 }11 H on; 314 }H H on, 315 $011330?}4-C1C5H4CHB on CH: 316 humanism OE our 317 CH3 homsmmmmmom-.. 0H error318 }11 H on,

CH i o n g oi sorcrmomcneu i H Example 320 mice when given orally asshown by their reaction to being touched lightly on the vibrissae (headwithdrawal 1'[2-(3'mdo1yl)ethynpiperazm? 4 reflex). When administeredorally in mice, they showed R R and X are H, m is 1, n 18 2].1-[2-(a-1ndolyl)- d. 1 {Vt d b t f th thyl]-4-benzyl piperazine (18.50.058 mole) prepared leno y 10 ac 111 y P y an .1 msm 0 e i th 1 3 d 1 101 1] 4 DZ 1 erazine pressor effects of epinephrine. Further evidence oftran: mm 6 U 0y )tyoxay e p quilizing and CNS. depressant activity forthe com prepared above in Example 90 was dissolved 1n absolute poundswas Shown by overt behavior Studies in monkeys ethanol g Over. gj izg q(oral) in which the compounds produced a taming effect, under a out PounS o y Ogen W1 Warming sedation, skeletal muscle relaxation, hypothermiaand When reduction was complete, the catalyst was removed catalepsy by gg a zz g i g f??? Oral toxicity studies in mice have shown that the LD yz agfijp pg gg g 3 i 0 C of the compounds is in the range from about 110mg./ kg. (corr 120 arouts lllylm rfngfi/kg. whelre L2 1s defiiigd astheldosle ata to 0 o t e anlma's att at partrc ar ose eve j for C14H19N31833 In Table 21 below which summarizes the data so-ob- Found- NE, 11011tained for a number of the compounds, the effective dose,

Example 321 ED of each of the compounds in each of the abovedescribedtests 1s given in the appropriate column where 1i -d yl 1 the headingsH.P.T., II.W.R. and A.S.T. represent the a 2 3, 4, 5 6 and X are m 15 1,hexobaroital potentiation test, head withdrawal reflex and H WasPrepared 'l r yadrenolytic screening test respectively, and in thecolumn yh y ly p r p p above In headed Over Behavoir, the letters T, s,R, H and c rep- EXamPIe .Reducfion was carried Outficcofdillg resenttaming, sedation, relaxation (muscle), hypothermia manipulativeprocedure described above in Example 320.

and catalepsy, respectively.

TABLE 21 Ex. H.P.T. H.W.R. .4511. LD50 Overt behavior EDso ED50 'EDso(mg/kg.) M.E.D. (mg/kg.) e-I e -I e) 11 161 S, T and H 64. 163113.813.!) 18. 515.1 13. 412.1 440 s, '1 r,o and H, 166-.-- s. 211. 59.1121 6518. 4 3,090 '1, o and 11, s. 167-.-- 4. 711.0 13.4135 28 15.6s, T and H, s; R and C 32. 170-.-- 6. 611.4 6. 511. 6 11. 313. 5 160 s,'1 and H, 4; R

and 0,16. 176---- s. 011.6 40112 4015.2 4, 006 s Silt]. H, s; o,

6 178.... 5410.7 21011.9 53. 518.8 500 s, T, n and o, 16. 180---- 6.811. 6 6. 511. 2 712 2, 680 161.--- 8.8=l=2.6 2217.6 57110.2 s, 1, o andH,

6 152-.-- 5. 610.7 6. 411.8 68114.7 220 e 1, and H, 183-.-- 3. 211.213.4140 731.2115 s, 1" and H, 16. 184---- s. 012. 7 43115. 0 2818.14101176 T, s and H, 64.

185---- 4611.1 4. 910. 84 5. 512.1 110 '1, s, o and 11,

. 32. 186.... 5.2118 16611.6 160128.!) '1, s, o and H,

16. 1217.... 13213.7 61114.2 254130.11 189.--- 7. 711. 1 14. 61s. 1 '1,o and H, 16. 160-.-- 5. 011.3 128 'r, n and H,

191---- 3. 716. 57 6. 512. 1 r, and H, 4. 194.--- 4717. 6 47117. 1225..-- 60114. 9 128 255---- 1021418 The compounds of Formula XV, inaddition to being useful as intermediates for the preparation of thecompounds of Formulae la, b and c, have also been shown to possess adepressant action on the central nervous system. They protect mice fromthe hind limb extensor component of maximal electroshock seizures. Theseresults indicate their usefulness as central nervous system depressants,and in particular as anticonvulsant agents. Thus 1-(2,6-dimethylphenyl)-2-piperazinone hydrochloride, prepared above in Example11, protected seven out of ten mice for one hour againstelectroshock-induced convulsions at a dose of 400 mg./kg.

The compounds of Formulae la, b and 0 can be prepared for use bydissolving under sterile conditions a salt form of the compounds inwater (or an equivalent amount of a non-toxic acid if the free base isused), or in a physiologically compatible aqueous medium such as saline,and stored in ampoules for intramuscuar injection. Alternatively, theycan be incorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvants'such as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like. Still further, the compounds can be formulatedfor oral administration in aqueous alcohol, glycol or oil solutions oroil-Water-emulsions in the same manner as conventional medicinalsubstances are prepared. When used as hypotensive agents they areformulated and used in the same manner as conventional hypotensiveagents, such as reserpine preparations, and indeed can be usedadvantageously in combination with such hypotensive agents.

When the compounds of Formula XV are used as anticonvulsant agents, theycan be prepared for oral administration in solid form either with orwithout the aid of a carrier. Thus, the compounds can be formulated inunit dosage form as tablets in combination With a suitable adjuvant suchas one or more of the following: calcium carbonate, starch, gelatin,talc, magnesium stearate, acacia, and the like; or alternatively, theycan be employed in capsule form either alone or admixed with anadjuvant. Alternatively, the compounds can be formulated for oraladministration as an aqueous suspension, aqueous alcohol solutions, oilsolutions, or oil-Water emulsions, in the same manner in whichconventional medicinal substances are formulate.

4Q I claim: 11. A member of the group consisting of compounds of theformula compounds of the formula and compounds of the formula 6. l l Iwherein R is a member of the group consisting of a hydrogen atom andfrom one to four substituents selected from the group consisting ofhalogen, lower-alkyl, loweralkoxy, hydroxy, methylenedioxy,ethylenedioxy, loweralkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl, trifiuoromethyl, lower-alkanoyloxy, benzyloxy, andbenzyloxy substituted by from one to three substituents selected fromthe group consisting of halogen, lower-alkyl, lower-alkoxy, hydroxy,methylenedioxy, ethylenedioxy, loWer-alkylmercapto, loWer-alkylsulfinyl,lower-alkylsulfonyl, trifluoromethyl, and lower-alkanoyloxy; R is amember of the group consisting of hydrogen, lower-alkyl,hydroXy-lower-alkyl, phenyl, benzyl, phenethyl, benzhydryl, cinnamyl,pyrimidyl, pyrazinytl, pyridyl, thiazolyl, oxazolyl, 1,3,5-triazinyl,and thienyl; R is a member of the group consisting of hydrogen,lower-alkyl, and phenyl; R is a member of the group consisting ofhydrogen, loWer-alkyl, phenyl, benzyl, phenethyl, and cinnamyl andwherein the benzene ring of the phenyl, benzyl, phenethyl, and cinnamylmoieties of the groups R R and R; can be substituted 'by from one to twosubstituents selected from the group consisting of halogen, lower-alkyl,hydroxy, lower-alkoxy, methylenedioxy, ethylenedioxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, andtrifluoromethyl; R and R each is a member of the group consisting ofhydrogen and loWer-allryl; X is a member of the group consisting ofhydrogen and hydroxyl; m is an integer from 1 to 2; and n is an integerfrom 1 to 7.

2. A compound of the formula wherein n is an integer from 1 to 7. 3. Acompound of the formula wherein R is lower-alkyl and n is an integerfrom 1 to 7.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA